U.S. patent application number 10/697703 was filed with the patent office on 2004-08-12 for novel nimesulide compositions.
This patent application is currently assigned to Elan Pharma International Ltd.. Invention is credited to Bosch, H. William, Wertz, Christian F..
Application Number | 20040156872 10/697703 |
Document ID | / |
Family ID | 46300261 |
Filed Date | 2004-08-12 |
United States Patent
Application |
20040156872 |
Kind Code |
A1 |
Bosch, H. William ; et
al. |
August 12, 2004 |
Novel nimesulide compositions
Abstract
The present invention provides nanoparticulate nimesulide
compositions. The compositions preferably comprise nimesulide and
at least one surface stabilizer adsorbed on or associated with the
surface of the nimesulide particles. The nanoparticulate nimesulide
particles preferably have an effective average particle size of
less than about 2000 nm. The invention also provides methods of
making and using nanoparticulate nimesulide compositions.
Inventors: |
Bosch, H. William; (Bryn
Mawr, PA) ; Wertz, Christian F.; (Brookhaven,
PA) |
Correspondence
Address: |
FOLEY AND LARDNER
SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
Elan Pharma International
Ltd.
|
Family ID: |
46300261 |
Appl. No.: |
10/697703 |
Filed: |
October 31, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10697703 |
Oct 31, 2003 |
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10276400 |
Jan 15, 2003 |
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10276400 |
Jan 15, 2003 |
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09572961 |
May 18, 2000 |
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6316029 |
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Current U.S.
Class: |
424/400 ;
424/489 |
Current CPC
Class: |
A61P 37/06 20180101;
A61P 11/14 20180101; A61P 31/04 20180101; A61P 31/10 20180101; A61P
43/00 20180101; A61P 25/22 20180101; A61P 25/06 20180101; A61P
31/12 20180101; A61P 25/20 20180101; A61K 9/145 20130101; A61P
13/12 20180101; A61K 9/2018 20130101; A61P 9/06 20180101; A61P
11/02 20180101; A61P 35/00 20180101; A61P 29/00 20180101; A61K
9/146 20130101; A61K 9/2054 20130101; A61P 19/08 20180101; A61K
9/1623 20130101; A61P 25/24 20180101; A61K 9/5192 20130101; A61P
11/06 20180101; A61P 25/08 20180101; A61P 13/08 20180101; A61P
19/02 20180101; A61K 9/1617 20130101; A61K 9/1652 20130101; A61P
1/08 20180101; A61P 9/00 20180101; A61P 13/00 20180101; A61K 9/2077
20130101; A61K 9/2081 20130101; A61P 9/12 20180101; A61P 37/08
20180101; A61K 9/0056 20130101; A61P 3/04 20180101; A61P 25/28
20180101; A61P 9/10 20180101; A61P 27/16 20180101; A61P 15/00
20180101; A61K 9/5161 20130101; A61P 1/12 20180101; A61P 7/02
20180101; A61P 33/10 20180101 |
Class at
Publication: |
424/400 ;
424/489 |
International
Class: |
A61K 009/14; A61K
009/00 |
Claims
We claim:
1. A nimesulide composition comprising: (a) particles of nimesulide
or a salt thereof, wherein the particles have an effective average
particle size of less than about 2000 nm; and (b) at least one
surface stabilizer.
2. The composition of claim 1, wherein the nimesulide is selected
from the group consisting of a crystalline phase, an amorphous
phase, a semi-crystalline phase, a semi-amorphous phase, and
mixtures thereof.
3. The composition of claim 1, wherein the effective average
particle size of the nimesulide particles is selected from the
group consisting of less than about 1900 nm, less than about 1800
nm, less than about 1700 nm, less than about 1600 nm, less than
about 1500 nm, less than about 1400 nm, less than about 1300 nm,
less than about 1200 nm, less than about 1100 nm, less than about
1000 nm, less than about 900 nm, less than about 800 nm, less than
about 700 nm, less than about 600 nm, less than about 500 nm, less
than about 400 nm, less than about 300 nm, less than about 250 nm,
less than about 200 nm, less than about 100 nm, less than about 75
nm, and less than about 50 nm.
4. The composition of claim 1, wherein the composition is
formulated for administration selected from the group consisting of
oral, pulmonary, rectal, opthalmic, colonic, parenteral,
intracisternal, intravaginal, intraperitoneal, local, buccal,
nasal, and topical administration.
5. The composition of claim 1 formulated into a dosage form
selected from the group consisting of liquid dispersions, oral
suspensions, gels, aerosols, ointments, creams, controlled release
formulations, fast melt formulations, lyophilized formulations,
tablets, capsules, delayed release formulations, extended release
formulations, pulsatile release formulations, and mixed immediate
release and controlled release formulations.
6. The composition of claim 1, wherein the composition further
comprises one or more pharmaceutically acceptable excipients,
carriers, or a combination thereof.
7. The composition of claim 1, wherein the nimesulide or a salt
thereof is present in an amount selected from the group consisting
of from about 99.5% to about 0.001%, from about 95% to about 0.1%,
and from about 90% to about 0.5%, by weight, based on the total
combined dry weight of the nimesulide or a salt thereof and at
least one surface stabilizer, not including other excipients.
8. The composition of claim 1, wherein the at least one surface
stabilizer is present in an amount selected from the group
consisting of from about 0.5% to about 99.999% by weight, from
about 5.0% to about 99.9% by weight, and from about 10% to about
99.5% by weight, based on the total combined dry weight of the
nimesulide or a salt thereof and at least one surface stabilizer,
not including other excipients.
9. The composition of claim 1, comprising two or more surface
stabilizers.
10. The composition of claim 1, wherein the surface stabilizer is
selected from the group consisting of an anionic surface
stabilizer, a cationic surface stabilizer, a zwitterionic surface
stabilizer, and an ionic surface stabilizer.
11. The composition of claim 10, wherein the at least one surface
stabilizer is selected from the group consisting of cetyl
pyridinium chloride, gelatin, casein, phosphatides, dextran,
glycerol, gum acacia, cholesterol, tragacanth, stearic acid,
benzalkonium chloride, calcium stearate, glycerol monostearate,
cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters,
polyoxyethylene alkyl ethers, polyoxyethylene castor oil
derivatives, polyoxyethylene sorbitan fatty acid esters,
polyethylene glycols, dodecyl trimethyl ammonium bromide,
polyoxyethylene stearates, colloidal silicon dioxide, phosphates,
sodium dodecylsulfate, carboxymethylcellulose calcium,
hydroxypropyl celluloses, hypromellose, carboxymethylcellulose
sodium, methylcellulose, hydroxyethylcellulose, hypromellose
phthalate, noncrystalline cellulose, magnesium aluminum silicate,
triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone,
4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and
formaldehyde, poloxamers; poloxamines, a charged phospholipid,
dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid,
sodium lauryl sulfate, alkyl aryl polyether sulfonates, mixtures of
sucrose stearate and sucrose distearate,
p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglucamide;
n-decyl .beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside;
n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside;
heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside;
n-heptyl P-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside;
nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside;
octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl
.beta.-D-thioglucopyranoside; lysozyme, PEG-phospholipid,
PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, and
random copolymers of vinyl acetate and vinyl pyrrolidone.
12. The composition of claim 10, wherein the at least one cationic
surface stabilizer is selected from the group consisting of a
polymer, a biopolymer, a polysaccharide, a cellulo sic, an
alginate, a nonpolymeric compound, and a pho spho lipid.
13. The composition of claim 10, wherein the surface stabilizer is
selected from the group consisting of cationic lipids,
polymethylmethacrylate trimethylammonium bromide, sulfonium
compounds, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate
dimethyl sulfate, hexadecyltrimethyl ammonium bromide, phosphonium
compounds, quarternary ammonium compounds,
benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl
ammonium chloride, coconut trimethyl ammonium bromide, coconut
methyl dihydroxyethyl ammonium chloride, coconut methyl
dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride,
decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl
hydroxyethyl ammonium chloride bromide, C.sub.12-15dimethyl
hydroxyethyl ammonium chloride, C.sub.12-15dimethyl hydroxyethyl
ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium
chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl
trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium
chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl
(ethenoxy).sub.4 ammonium chloride, lauryl dimethyl
(ethenoxy).sub.4 ammonium bromide, N-alkyl
(C.sub.12-18)dimethylbenzyl ammonium chloride, N-alkyl
(C.sub.14-18)dimethyl-benzyl ammonium chloride,
N-tetradecylidmethylbenzy- l ammonium chloride monohydrate,
dimethyl didecyl ammonium chloride, N-alkyl and (C.sub.12-14)
dimethyl 1-napthylmethyl ammonium chloride, trimethylammonium
halide, alkyl-trimethylammonium salts, dialkyl-dimethylammonium
salts, lauryl trimethyl ammonium chloride, ethoxylated
alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl
ammonium salt, dialkylbenzene dialkylammonium chloride,
N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl
ammonium, chloride monohydrate, N-alkyl(C.sub.12-14) dimethyl
1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium
chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl
ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl
benzyl dimethyl ammonium bromide, C.sub.12 trimethyl ammonium
bromides, C.sub.15 trimethyl ammonium bromides, C.sub.17 trimethyl
ammonium bromides, dodecylbenzyl triethyl ammonium chloride,
poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium
chlorides, alkyldimethylammonium halogenides, tricetyl methyl
ammonium chloride, decyltrimethylammonium bromide,
dodecyltriethylammonium bromide, tetradecyltrimethylammonium
bromide, methyl trioctylammonium chloride, POLYQUAT 10.TM.,
tetrabutylammonium bromide, benzyl trimethylammonium bromide,
choline esters, benzalkonium chloride, stearalkonium chloride
compounds, cetyl pyridinium bromide, cetyl pyridinium chloride,
halide salts of quaternized polyoxyethylalkylamines, MIRAPOL.TM.,
ALKAQUAT.TM., alkyl pyridinium salts; amines, amine salts, amine
oxides, imide azolinium salts, protonated quaternary acrylamides,
methylated quaternary polymers, and cationic guar.
14. The composition of claim 1, comprising as a surface stabilizer
a random copolymer of vinyl acetate and vinyl pyrrolidone,
hydroxypropylmethyl cellulose, or tyloxapol.
15. The composition of any of claims 10, 12, or 13, wherein the
composition is bioadhesive.
16. The composition of claim 1, wherein the T.sub.max of the
nimesulide, when assayed in the plasma of a mammalian subject
following administration, is less than the T.sub.max for a
conventional, non-nanoparticulate form of nimesulide, administered
at the same dosage.
17. The composition of claim 16, wherein the T.sub.max is selected
from the group consisting of not greater than about 90%, not
greater than about 80%, not greater than about 70%, not greater
than about 60%, not greater than about 50%, not greater than about
30%, not greater than about 25%, not greater than about 20%, not
greater than about 15%, and not greater than about 10% of the
T.sub.max, exhibited by a non-nanoparticulate formulation of
nimesulide, administered at the same dosage.
18. The composition of claim 1, wherein the C.sub.max of the
nimesulide, when assayed in the plasma of a mammalian subject
following administration, is greater than the C.sub.max for a
conventional, non-nanoparticulate form of nimesulide, administered
at the same dosage.
19. The composition of claim 18, wherein the C.sub.max is selected
from the group consisting of at least about 10%, at least about
20%, at least about 30%, at least about 40%, at least about 50%, at
least about 60%, at least about 70%, at least about 80%, at least
about 90%, and at least about 100% greater than the C.sub.max
exhibited by a non-nanoparticulate formulation of nimesulide,
administered at the same dosage.
20. The composition of claim 1, wherein the AUC of the nimesulide,
when assayed in the plasma of a mammalian subject following
administration, is greater than the AUC for a conventional,
non-nanoparticulate form of nimesulide, administered at the same
dosage.
21. The composition of claim 20, wherein the AUC is selected from
the group consisting of at least about 10%, at least about 20%, at
least about 30%, at least about 40%, at least about 50%, at least
about 60%, at least about 70%, at least about 80%, at least about
90%, and at least about 100% greater than the AUC exhibited by a
non-nanoparticulate formulation of nimesulide, administered at the
same dosage.
22. The composition of claim 1 which does not produce significantly
different absorption levels when administered under fed as compared
to fasting conditions.
23. The composition of claim 22, wherein the difference in
absorption of the nimesulide composition of the invention, when
administered in the fed versus the fasted state, is selected from
the group consisting of less than about 100%, less than about 90%,
less than about 80%, less than about 70%, less than about 60%, less
than about 50%, less than about 40%, less than about 30%, less than
about 25%, less than about 20%, less than about 15%, less than
about 10%, less than about 5%, and less than about 3%.
24. The composition of claim 1, wherein administration of the
composition to a subject in a fasted state is bioequivalent to
administration of the composition to a subject in a fed state, when
administered to a human.
25. The composition of claim 24, wherein "bioequivalency" is
established by a 90% Confidence Interval of between 0.80 and 1.25
for both C.sub.max and AUC, when administered to a human.
26. The composition of claim 24, wherein "bioequivalency" is
established by a 90% Confidence Interval of between 0.80 and 1.25
for AUC and a 90% Confidence Interval of between 0.70 to 1.43 for
C.sub.max, when administered to a human.
27. The composition of claim 1, further comprising at least one
additional nimesulide composition having an effective average
particle size which is different that the effective average
particle size of the nimesulide composition of claim 1.
28. The composition of claim 1, wherein upon administration the
composition redisperses such that the nimesulide particles have an
effective average particle size of less than about 2000 nm.
29. The composition of claim 28, wherein upon administration the
composition redisperses such that the nimesulide particles have an
effective average particle size selected from the group consisting
of less than about 1900 nm, less than about 1800 nm, less than
about 1700 nm, less than about 1600 nm, less than about 1500 nm,
less than about 1400 nm, less than about 1300 nm, less than about
1200 run, less than about 1100 nm, less than about 1000 nm, less
than about 900 nm, less than about 800 nm, less than about 700 nm,
less than about 600 nm, less than about 500 nm, less than about 400
nm, less than about 300 run, less than about 250 nm, less than
about 200 nm, less than about 150 nm, less than about 100 nm, less
than about 75 nm, and less than about 50 mm.
30. The composition of claim 1, wherein the composition redisperses
in a biorelevant media such that the nimesulide particles have an
effective average particle size of less than about 2 microns.
31. The composition of claim 30, wherein the composition
redisperses in a biorelevant media such that the nimesulide
particles have an effective average particle size selected from the
group consisting of less than about 1900 nm, less than about 1800
nm, less than about 1700 nm, less than about 1600 nm, less than
about 1500 nm, less than about 1400 nm, less than about 1300 nm,
less than about 1200 nm, less than about 1100 nm, less than about
1000 nm, less than about 900 nm, less than about 800 nm, less than
about 700 nm, less than about 600 nm, less than about 500 nm, less
than about 400 nm, less than about 300 nm, less than about 250 nm,
less than about 200 nm, less than about 150 nm, less than about 100
nm, less than about 75 nm, and less than about 50 nm.
32. The composition of claim 1 formulated into a liquid dosage
form, wherein the dosage form has a viscosity of less than about
2000 mPa.multidot.s, measured at 20.degree. C., at a shear rate of
0.1 (1/s).
33. The composition of claim 32, having a viscosity at a shear rate
of 0.1 (1/s) selected from the group consisting of from about 2000
mPa.multidot.s to about 1 mPa.multidot.s, from about 1900
mPa.multidot.s to about 1 mPa.multidot.s, from about 1800
mPa.multidot.s to about 1 mPa.multidot.s, from about 1700
mPa.multidot.s to about 1 mPa.multidot.s, from about 1600
mPa.multidot.s to about 1 mPa.multidot.s, from about 1500
mPa.multidot.s to about 1 mPa.multidot.s, from about 1400
mPa.multidot.s to about 1 mPa.multidot.s, from about 1300
mPa.multidot.s to about 1 mPa-s, from about 1200 mPa.multidot.s to
about 1 mPa.multidot.s, from about 1100 mPa-s to about 1
mPa.multidot.s, from about 1000 mPa.multidot.s to about 1
mPa.multidot.s, from about 900 mPa.multidot.s to about 1
mPa.multidot.s, from about 800 mPa.multidot.s to about 1
mPa.multidot.s, from about 700 mPa.multidot.s to about 1
mPa.multidot.s, from about 600 mPa.multidot.s to about 1
mPa.multidot.s, from about 500 mPa.multidot.s to about 1
mPa.multidot.s, from about 400 mPa.multidot.s to about 1
mPa.multidot.s, from about 300 mPa.multidot.s to about 1
mPa.multidot.s, from about 200 mPa.multidot.s to about 1
mPa.multidot.s, from about 175 mPa.multidot.s to about 1
mPa.multidot.s, from about 150 mPa.multidot.s to about 1
mPa.multidot.s, from about 125 mPa.multidot.s to about 1
mPa.multidot.s, from about 100 mPa.multidot.s to about 1
mPa.multidot.s, from about 75 mPa.multidot.s to about 1
mPa.multidot.s, from about 50 mPa.multidot.s to about 1
mPa.multidot.s, from about 25 mPa.multidot.s to about 1
mPa.multidot.s, from about 15 mPa.multidot.s to about 1
mPa.multidot.s, from about 10 mPa.multidot.s to about 1
mPa.multidot.s, and from about 5 mPa.multidot.s to about 1
mPa.multidot.s.
34. The composition of claim 32, wherein the viscosity of the
dosage form is selected from the group consisting of less than
about {fraction (1/200)}, less than about {fraction (1/100)}, less
than about {fraction (1/50)}, less than about {fraction (1/25)},
and less than about {fraction (1/10)} of the viscosity of a liquid
dosage form of conventional non-nanoparticulate nimesulide at about
the same concentration per ml of nimesulide.
35. The composition of claims 32, wherein the viscosity of the
dosage form is selected from the group consisting of less than
about 5%, less than about 10%, less than about 15%, less than about
20%, less than about 25%, less than about 30%, less than about 35%,
less than about 40%, less than about 45%, less than about 50%, less
than about 55%, less than about 60%, less than about 65%, less than
about 70%, less than about 75%, less than about 80%, less than
about 85%, and less than about 90% of the viscosity of a liquid
dosage form of conventional, non-nanoparticulate nimesulide at
about the same concentration per ml of nimesulide.
36. The composition of claim 1, additionally comprising one or more
non-nimesulide active agents.
37. The method of claim 36, wherein said non-nimesulide active
agent is selected from the group consisting of an analgesic, an
anti-inflammatory, an antipyretic, and a vasomodulator.
38. The composition of claim 36, wherein said non-nimesulide active
agent is selected from the group consisting of nutraceuticals,
proteins, peptides, nucleotides, amino acids, anti-obesity drugs,
central nervous system stimulants, carotenoids, corticosteroids,
elastase inhibitors, anti-fungals, oncology therapies,
anti-emetics, analgesics, cardiovascular agents, anti-inflammatory
agents, NSAIDs, non-nimesulide COX-2 inhibitors, anthelmintics,
anti-arrhythmic agents, antibiotics, anticoagulants,
antidepressants, antidiabetic agents, antiepileptics,
antihistamines, antihypertensive agents, antimuscarinic agents,
antimycobacterial agents, antineoplastic agents,
immunosuppressants, antithyroid agents, antiviral agents,
anxiolytics, sedatives, astringents, alpha-adrenergic receptor
blocking agents, beta-adrenoceptor blocking agents, blood products
and substitutes, cardiac inotropic agents, contrast media,
corticosteroids, cough suppressants, diagnostic agents, diagnostic
imaging agents, diuretics, dopaminergics, haemostatics,
immunological agents, lipid regulating agents, muscle relaxants,
parasymPathomimetics, parathyroid calcitonin and biphosphonates,
prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergic
agents, stimulants and anoretics, symPathomimetics, thyroid agents,
vasodilators, vasomodulators, and xanthines.
39. The composition of claim 38, wherein said nutraceutical is
selected from the group consisting of lutein, folic acid, fatty
acids, fruit extracts, vegetable extracts, vitamin supplements,
mineral supplements, phosphatidylserine, lipoic acid, melatonin,
glucosamine/chondroitin, Aloe Vera, Guggul, glutamine, amino acids,
green tea, lycopene, whole foods, food additives, herbs,
phytonutrients, antioxidants, flavonoid constituents of fruits,
evening primrose oil, flax seeds, fish oils, marine animal oils,
and probiotics.
40. The composition of claim 36, wherein said non-nimesulide active
agent is selected from the group consisting of aceclofenac,
acemetacin, e-acetamidocaproic acid, acetaminophen, acetaminosalol,
acetanilide, acetylsalicylic acid, S-adenosylmethionine,
alclofenac, alfentanil, allylprodine, alminoprofen, aloxiprin,
alphaprodine, aluminum bis(acetylsalicylate), amfenac,
aminochlorthenoxazin, 3-amino-4-hydroxybutyric acid,
2-amino-4-picoline, aminopropylon, aminopyrine, amixetrine,
ammonium salicylate, ampiroxicam, amtolmetin guacil, anileridine,
antipyrine, antipyrine salicylate, antrafenine, apazone, bendazac,
benorylate, benoxaprofen, benzpiperylon, benzydamine,
benzylmorphine, bermoprofen, bezitramide, .alpha.-bisabolol,
bromfenac, p-bromoacetanilide, 5-bromosalicylic acid acetate,
bromosaligenin, bucetin, bucloxic acid, bucolome, bufexamac,
bumadizon, buprenorphine, butacetin, butibufen, butophanol, calcium
acetylsalicylate, carbamazepine, carbiphene, carprofen, carsalam,
chlorobutanol, chlorthenoxazin, choline salicylate, cinchophen,
cinmetacin, ciramadol, clidanac, clometacin, clonitazene, clonixin,
clopirac, clove, codeine, codeine methyl bromide, codeine
phosphate, codeine sulfate, cropropamide, crotethamide,
desomorphine, dexoxadrol, dextromoramide, dezocine, diampromide,
diclofenac sodium, difenamizole, difenpiramide, diflunisal,
dihydrocodeine, dihydrocodeinone enol acetate, dihydromorphine,
dihydroxyaluminum acetylsalicylate, dimenoxadol, dimepheptanol,
dimethylthiambutene, dioxaphetyl butyrate, dipipanone, diprocetyl,
dipyrone, ditazol, droxicam, emorfazone, enfenamic acid, epirizole,
eptazocine, etersalate, ethenzamide, ethoheptazine, ethoxazene,
ethylmethylthiambutene, ethylmorphine, etodolac, etofenamate,
etonitazene, eugenol, felbinac, fenbufen, fenclozic acid, fendosal,
fenoprofen, fentanyl, fentiazac, fepradinol, feprazone,
floctafenine, flufenamic acid, flunoxaprofen, fluoresone,
flupirtine, fluproquazone, flurbiprofen, fosfosal, gentisic acid,
glafenine, glucametacin, glycol salicylate, guaiazulene,
hydrocodone, hydromorphone, hydroxypethidine, ibufenac, ibuprofen,
ibuproxam, imidazole salicylate, indomethacin, indoprofen,
isofezolac, isoladol, isomethadone, isonixin, isoxepac, isoxicam,
ketobemidone, ketoprofen, ketorolac, p-lactophenetide, lefetamine,
levorphanol, lofentanil, lonazolac, lomoxicam, loxoprofen, lysine
acetylsalicylate, magnesium acetylsalicylate, meclofenamic acid,
mefenamic acid, meperidine, meptazinol, mesalamine, metazocine,
methadone hydrochloride, methotrimeprazine, metiazinic acid,
metofoline, metopon, mofebutazone, mofezolac, morazone, morphine,
morphine hydrochloride, morphine sulfate, morpholine salicylate,
myrophine, nabumetone, nalbuphine, 1-naphthyl salicylate, naproxen,
narceine, nefopam, nicomorphine, nifenazone, niflumic acid,
nimesulide, 5'-nitro-2'-propoxyacetanilide, norlevorphanol,
normethadone, normorphine, norpipanone, olsalazine, opium,
oxaceprol, oxametacine, oxaprozin, oxycodone, oxymorphone,
oxyphenbutazone, papaveretum, paranyline, parsalmide, pentazocine,
perisoxal, phenacetin, phenadoxone, phenazocine, phenazopyridine
hydrochloride, phenocoll, phenoperidine, phenopyrazone, phenyl
acetylsalicylate, phenylbutazone, phenyl salicylate, phenyramidol,
piketoprofen, piminodine, pipebuzone, piperylone, piprofen,
pirazolac, piritramide, piroxicam, pranoprofen, proglumetacin,
proheptazine, promedol, propacetamol, propiram, propoxyphene,
propyphenazone, proquazone, protizinic acid, ramifenazone,
remifentanil, rimazolium metilsulfate, salacetamide, salicin,
salicylamide, salicylamide o-acetic acid, salicylsulfuric acid,
salsalte, salverine, simetride, sodium salicylate, sufentanil,
sulfasalazine, sulindac, superoxide dismutase, suprofen,
suxibuzone, talniflumate, tenidap, tenoxicam, terofenamate,
tetrandrine, thiazolinobutazone, tiaprofenic acid, tiaramide,
tilidine, tinoridine, tolfenamic acid, tolmetin, tramadol,
tropesin, viminol, xenbucin, ximoprofen, zaltoprofen, and
zomepirac.
41. The composition of claim 38, in which the vasomodulator is
selected from the group consisting of caffeine, theobromine, and
theophylline.
42. The composition of claim 38, in which the NSAID is selected
from the group consisting of nabumetone, tiaramide, proquazone,
bufexamac, flumizole, epirazole, tinoridine, timegadine, dapsone,
aspirin, diflunisal, benorylate, fosfosal, diclofenac, alclofenac,
fenclofenac, etodolac, indomethacin, sulindac, tolmetin, fentiazac,
tilomisole, carprofen, fenbufen, flurbiprofen, ketoprofen,
oxaprozin, suprofen, tiaprofenic acid, ibuprofen, naproxen,
fenoprofen, indoprofen, pirprofen, flufenamic, mefenamic,
meclofenamic, niflumic, oxyphenbutazone, phenylbutazone, apazone,
feprazone, piroxicam, sudoxicam, isoxicam, and tenoxicam.
43. The composition of claim 38, in which the COX-2 inhibitor is
selected from the group consisting of celecoxib, rofecoxib,
meloxicam, valdecoxib, parecoxib, etoricoxib, SC-236, NS-398,
SC-58125, SC-57666, SC-558, SC-560, etodolac, DFU, monteleukast,
L-745337, L-761066, L-761000, L-748780, DUP-697, PGV 20229,
iguratimod, BF 389, CL 1004, PD 136005, PD 142893, PD 138387, PD
145065, flurbiprofen, nabumetone, flosulide, piroxicam, diclofenac,
lumiracoxib, D 1367, R 807, JTE-522, FK-3311, FK 867, FR 140423, FR
115068, GR 253035, RWJ 63556, RWJ 20485, ZK 38997, S 2474,
zomepirac analogs, RS 104894, SC 41930, pranlukast, SB 209670, and
APHS
44. The composition of claim 1, which has been sterile
filtered.
45. A method of making a nimesulide composition comprising
contacting particles of nimesulide or a salt thereof with at least
one surface stabilizer for a time and under conditions sufficient
to provide a nimesulide composition having an effective average
particle size of less than about 2000 nm.
46. The method of claim 45, wherein said contacting comprises
grinding.
47. The method of claim 46, wherein said grinding comprises wet
grinding.
48. The method of claim 45, wherein said contacting comprises
homogenizing.
49. The method of claim 45, wherein said contacting comprises: (a)
dissolving the particles of nimesulide or a salt thereof in a
solvent; (b) adding the resulting nimesulide solution to a solution
comprising at least one surface stabilizer; and (c) precipitating
the solubilized nimesulide having at least one surface stabilizer
adsorbed on the surface thereof by the addition thereto of a
non-solvent.
50. The method of claim 45, wherein the nimesulide or a salt
thereof is selected from the group consisting of a crystalline
phase, an amorphous phase, a semi-crystalline phase, a
semi-amorphous phase, and mixtures thereof.
51. The method of claim 45, wherein the effective average particle
size of the nimesulide particles is selected from the group
consisting of less than about 1900 nm, less than about 1800 nm,
less than about 1700 nm, less than about 1600 nm, less than about
1500 nm, less than about 1000 nm, less than about 1400 nm, less
than about 1300 nm, less than about 1200 nm, less than about 1100
nm, less than about 900 nm, less than about 800 nm, less than about
700 nm, less than about 600 nm, less than about 500 nm, less than
about 400 nm, less than about 300 nm, less than about 250 nm, less
than about 200 nm, less than about 100 nm, less than about 75 nm,
and less than about 50 nm.
52. The method of claim 45, wherein the composition is formulated
for administration selected from the group consisting of oral,
pulmonary, rectal, opthalmic, colonic, parenteral, intracisternal,
intravaginal, intraperitoneal, local, buccal, nasal, and topical
administration.
53. The method of claim 45, wherein the composition further
comprises one or more pharmaceutically acceptable excipients,
carriers, or a combination thereof.
54. The method of claim 45, wherein the nimesulide or a salt
thereof is present in an amount selected from the group consisting
of from about 99.5% to about 0.001%, from about 95% to about 0.1%,
and from about 90% to about 0.5%, by weight, based on the total
combined dry weight of the nimesulide or a salt thereof and at
least one surface stabilizer, not including other excipients.
55. The method of claim 45, wherein the at least one surface
stabilizer is present in an amount selected from the group
consisting of from about 0.5% to about 99.999%, from about 5.0% to
about 99.9%, and from about 10% to about 99.5% by weight, based on
the total combined dry weight of the nimesulide or a salt thereof
and at least one surface stabilizer, not including other
excipients.
56. The method of claim 45, comprising at two surface
stabilizers.
57. The method of claim 45, wherein the surface stabilizer is
selected from the group consisting of an anionic surface
stabilizer, a cationic surface stabilizer, a zwitterionic surface
stabilizer, and an ionic surface stabilizer.
58. The method of claim 57, wherein the at least one surface
stabilizer is selected from the group consisting of cetyl
pyridinium chloride, gelatin, casein, phosphatides, dextran,
glycerol, gum acacia, cholesterol, tragacanth, stearic acid,
benzalkonium chloride, calcium stearate, glycerol monostearate,
cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters,
polyoxyethylene alkyl ethers, polyoxyethylene castor oil
derivatives, polyoxyethylene sorbitan fatty acid esters,
polyethylene glycols, dodecyl trimethyl ammonium bromide,
polyoxyethylene stearates, colloidal silicon dioxide, phosphates,
sodium dodecylsulfate, carboxymethylcellulose calcium,
hydroxypropyl celluloses, hypromellose, carboxymethylcellulose
sodium, methylcellulose, hydroxyethylcellulose, hypromellose
phthalate, noncrystalline cellulose, magnesium aluminum silicate,
triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone,
4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and
formaldehyde, poloxamers; poloxamines, a charged phospholipid,
dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid,
sodium lauryl sulfate, alkyl aryl polyether sulfonates, mixtures of
sucrose stearate and sucrose distearate,
p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglucamide;
n-decyl .beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside;
n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside;
heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucop- yranoside;
n-heptyl .beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside;
nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside;
octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl
.beta.-D-thioglucopyranoside; lysozyme, PEG-phospholipid,
PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A,
PEG-vitamin E, and random copolymers of vinyl acetate and vinyl
pyrrolidone.
59. The method of claim 57, wherein the at least one cationic
surface stabilizer is selected from the group consisting of a
polymer, a biopolymer, a polysaccharide, a cellulosic, an alginate,
a nonpolymeric compound, and a phospholipid.
60. The method of claim 57, wherein the surface stabilizer is
selected from the group consisting of cationic lipids,
polymethylmethacrylate trimethylammonium bromide, sulfonium
compounds, polyvinylpyrrolidone-2-di- methylaminoethyl methacrylate
dimethyl sulfate, hexadecyltrimethyl ammonium bromide, phosphonium
compounds, quarternary ammonium compounds,
benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl
ammonium chloride, coconut trimethyl ammonium bromide, coconut
methyl dihydroxyethyl ammonium chloride, coconut methyl
dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride,
decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl
hydroxyethyl ammonium chloride bromide, C.sub.12-15dimethyl
hydroxyethyl ammonium chloride, C.sub.12-15dimethyl hydroxyethyl
ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium
chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl
trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium
chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl
(ethenoxy).sub.4 ammonium chloride, lauryl dimethyl
(ethenoxy).sub.4 ammonium bromide, N-alkyl
(C.sub.12-18)dimethylbenzyl ammonium chloride, N-alkyl
(C.sub.14-18)dimethyl-benzyl ammonium chloride,
N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl
didecyl ammonium chloride, N-alkyl and (C.sub.12-14) dimethyl
1-napthylmethyl ammonium chloride, trimethylammonium halide,
alkyl-trimethylammonium salts, dialkyl-dimethylammonium salts,
lauryl trimethyl ammonium chloride, ethoxylated
alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl
ammonium salt, dialkylbenzene dialkylammonium chloride,
N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl
ammonium, chloride monohydrate, N-alkyl(C.sub.12-14) dimethyl
1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium
chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl
ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl
benzyl dimethyl ammonium bromide, C.sub.12 trimethyl ammonium
bromides, C.sub.15 trimethyl ammonium bromides, C.sub.17 trimethyl
ammonium bromides, dodecylbenzyl triethyl ammonium chloride,
poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium
chlorides, alkyldimethylammonium halogenides, tricetyl methyl
ammonium chloride, decyltrimethylammonium bromide,
dodecyltriethylammonium bromide, tetradecyltrimethylammonium
bromide, methyl trioctylammonium chloride, POLYQUAT 10.TM.,
tetrabutylammonium bromide, benzyl trimethylammonium bromide,
choline esters, benzalkonium chloride, stearalkonium chloride
compounds, cetyl pyridinium bromide, cetyl pyridinium chloride,
halide salts of quaternized polyoxyethylalkylamines, MIRAPOL.TM.,
ALKAQUAT.TM., alkyl pyridinium salts; amines, amine salts, amine
oxides, imide azolinium salts, protonated quaternary acrylamides,
methylated quaternary polymers, and cationic guar.
61. The method of claim 45, utilizing as a surface stabilizer a
random copolymer of vinyl acetate and vinyl pyrrolidone,
hydroxypropylmethyl cellulose, or tyloxapol.
62. The method of any of claims 57, 59, or 60, wherein the
composition is bioadhesive.
63. A method of treating a subject in need comprising administering
to the subject an effective amount of a composition comprising: (a)
particles of nimesulide or a salt thereof, wherein the nimesulide
particles have an effective average particle size of less than
about 2000 nm; and (b) at least one surface stabilizer.
64. The method of claim 63, wherein the nimesulide or a salt
thereof is selected from the group consisting of a crystalline
phase, an amorphous phase, a semi-crystalline phase, a
semi-amorphous phase, and mixtures thereof.
65. The method of claim 63, wherein the effective average particle
size of the nimesulide particles is selected from the group
consisting of less than about 1900 nm, less than about 1800 nm,
less than about 1700 nm, less than about 1600 nm, less than about
1500 nm, less than about 1400 nm, less than about 1300 nm, less
than about 1200 nm, less than about 1100 nm, less than about 1000
nm, less than about 900 nm, less than about 800 nm, less than about
700 nm, less than about 600 nm, less than about 500 nm, less than
about 400 nm, less than about 300 run, less than about 250 mm, less
than about 200 nm, less than about 100 nm, less than about 75 nm,
and less than about 50 nm.
66. The method of claim 63, wherein the composition is formulated
for administration selected from the group consisting of oral,
pulmonary, rectal, opthalmic, colonic, parenteral, intracisternal,
intravaginal, intraperitoneal, local, buccal, nasal, and topical
administration.
67. The method of claim 63, wherein the composition is a dosage
form selected from the group consisting of liquid dispersions, oral
suspensions, gels, aerosols, ointments, creams, controlled release
formulations, fast melt formulations, lyophilized formulations,
tablets, capsules, delayed release formulations, extended release
formulations, pulsatile release formulations, and mixed immediate
release and controlled release formulations.
68. The method of claim 63, wherein the composition further
comprises one or more pharmaceutically acceptable excipients,
carriers, or a combination thereof.
69. The method of claim 63, wherein the nimesulide or a salt
thereof is present in an amount selected from the group consisting
of from about 99.5% to about 0.001%, from about 95% to about 0.1%,
and from about 90% to about 0.5%, by weight, based on the total
combined dry weight of the nimesulide or a salt thereof and at
least one surface stabilizer, not including other excipients.
70. The method of claim 63, wherein the at least one surface
stabilizer is present in an amount selected from the group
consisting of from about 0.5% to about 99.999% by weight, from
about 5.0% to about 99.9% by weight, and from about 10% to about
99.5% by weight, based on the total combined dry weight of the
nimesulide or a salt thereof and at least one surface stabilizer,
not including other excipients.
71. The method of claim 63, comprising at two surface
stabilizers.
72. The method of claim 63, wherein the surface stabilizer is
selected from the group consisting of an anionic surface
stabilizer, a cationic surface stabilizer, a zwitterionic surface
stabilizer, and an ionic surface stabilizer.
73. The method of claim 72, wherein the at least one surface
stabilizer is selected from the group consisting of cetyl
pyridinium chloride, gelatin, casein, phosphatides, dextran,
glycerol, gum acacia, cholesterol, tragacanth, stearic acid,
benzalkonium chloride, calcium stearate, glycerol monostearate,
cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters,
polyoxyethylene alkyl ethers, polyoxyethylene castor oil
derivatives, polyoxyethylene sorbitan fatty acid esters,
polyethylene glycols, dodecyl trimethyl ammonium bromide,
polyoxyethylene stearates, colloidal silicon dioxide, phosphates,
sodium dodecylsulfate, carboxymethylcellulose calcium,
hydroxypropyl celluloses, hypromellose, carboxymethylcellulose
sodium, methylcellulose, hydroxyethylcellulose, hypromellose
phthalate, noncrystalline cellulose, magnesium aluminum silicate,
triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone,
4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and
formaldehyde, poloxamers; poloxamines, a charged phospholipid,
dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid,
sodium lauryl sulfate, alkyl aryl polyether sulfonates, mixtures of
sucrose stearate and sucrose distearate,
p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglucamide;
n-decyl .beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside;
n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside;
heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucop- yranoside;
n-heptyl .beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside;
nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside;
octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl
.beta.-D-thioglucopyranoside; lysozyme, PEG-phospholipid,
PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A,
PEG-vitamin E, and random copolymers of vinyl acetate and vinyl
pyrrolidone.
74. The method of claim 72, wherein the at least one cationic
surface stabilizer is selected from the group consisting of a
polymer, a biopolymer, a polysaccharide, a cellulosic, an alginate,
a nonpolymeric compound, and a phospholipid.
75. The method of claim 72, wherein the surface stabilizer is
selected from the group consisting of benzalkonium chloride,
polymethylmethacrylate trimethylammonium bromide,
polyvinylpyrrolidone-2-- dimethylaminoethyl methacrylate dimethyl
sulfate, hexadecyltrimethyl ammonium bromide, cationic lipids,
sulfonium compounds, phosphonium compounds, quarternary ammonium
compounds, benzyl-di(2-chloroethyl)ethyla- mmonium bromide, coconut
trimethyl ammonium chloride, coconut trimethyl ammonium bromide,
coconut methyl dihydroxyethyl ammonium chloride, coconut methyl
dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride,
decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl
hydroxyethyl ammonium chloride bromide, C.sub.12-15dimethyl
hydroxyethyl ammonium chloride, C.sub.12-15dimethyl hydroxyethyl
ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium
chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl
trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium
chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl
(ethenoxy).sub.4 ammonium chloride, lauryl dimethyl
(ethenoxy).sub.4 ammonium bromide, N-alkyl
(C.sub.12-18)dimethylbenzyl ammonium chloride, N-alkyl
(C.sub.14-18)dimethyl-benzyl ammonium chloride,
N-tetradecylidmethylbenzy- l ammonium chloride monohydrate,
dimethyl didecyl ammonium chloride, N-alkyl and (C.sub.12-14)
dimethyl 1-napthylmethyl ammonium chloride, trimethylammonium
halide, alkyl-trimethylammonium salts, dialkyl-dimethylammonium
salts, lauryl trimethyl ammonium chloride, ethoxylated
alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl
ammonium salt, dialkylbenzene dialkylammonium chloride,
N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl
ammonium, chloride monohydrate, N-alkyl(C.sub.12-14) dimethyl
1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium
chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl
ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl
benzyl dimethyl ammonium bromide, C.sub.12 trimethyl ammonium
bromides, C.sub.15 trimethyl ammonium bromides, C.sub.17 trimethyl
ammonium bromides, dodecylbenzyl triethyl ammonium chloride,
poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium
chlorides, alkyldimethylammonium halogenides, tricetyl methyl
ammonium chloride, decyltrimethylammonium bromide,
dodecyltriethylammonium bromide, tetradecyltrimethylammonium
bromide, methyl trioctylammonium chloride, POLYQUAT 10.TM.,
tetrabutylammonium bromide, benzyl trimethylammonium bromide,
choline esters, benzalkonium chloride, stearalkonium chloride
compounds, cetyl pyridinium bromide, cetyl pyridinium chloride,
halide salts of quaternized polyoxyethylalkylamines, MIRAPOL.TM.,
ALKAQUAT.TM., alkyl pyridinium salts; amines, amine salts, amine
oxides, imide azolinium salts, protonated quaternary acrylamides,
methylated quaternary polymers, and cationic guar.
76. The method of claim 63, utilizing as a surface stabilizer a
random copolymer of vinyl acetate and vinyl pyrrolidone,
hydroxypropylmethyl cellulose, or tyloxapol.
77. The method of any of claims 72, 74, or 75, wherein the
composition is bioadhesive.
78. The method of claim 63, wherein administration of the
nimesulide composition does not produce significantly different
absorption levels when administered under fed as compared to
fasting conditions, when administered to a human.
79. The method of claim 78, wherein the difference in absorption of
the nimesulide composition of the invention, when administered in
the fed versus the fasted state, is selected from the group
consisting of less than about 100%, less than about 90%, less than
about 80%, less than about 70%, less than about 60%, less than
about 50%, less than about 40%, less than about 30%, less than
about 25%, less than about 20%, less than about 15%, less than
about 10%, less than about 5%, and less than about 3%.
80. The method of claim 63, wherein administration of the
composition to a subject in a fasted state is bioequivalent to
administration of the composition to a subject in a fed state, when
administered to a human.
81. The method of claim 80, wherein "bioequivalency" is established
by a 90% Confidence Interval of between 0.80 and 1.25 for both
C.sub.max and AUC, when administered to a human.
82. The method of claim 80, wherein "bioequivalency" is established
by a 90% Confidence Interval of between 0.80 and 1.25 for AUC and a
90% Confidence Interval of between 0.70 to 1.43 for Cmax, when
administered to a human.
83. The method of claim 63, wherein the T.sub.max of the
nimesulide, when assayed in the plasma of a mammalian subject
following administration, is less than the T.sub.max for a
conventional, non-nanoparticulate form of nimesulide, administered
at the same dosage.
84. The method of claim 83, wherein the T.sub.max is selected from
the group consisting of not greater than about 90%, not greater
than about 80%, not greater than about 70%, not greater than about
60%, not greater than about 50%, not greater than about 30%, not
greater than about 25%, not greater than about 20%, not greater
than about 15%, and not greater than about 10% of the T.sub.max,
exhibited by a non-nanoparticulate formulation of nimesulide,
administered at the same dosage.
85. The method of claim 63, wherein the Cmax of the nimesulide,
when assayed in the plasma of a mammalian subject following
administration, is greater than the Cmax for a conventional,
non-nanoparticulate form of nimesulide, administered at the same
dosage.
86. The method of claim 85, wherein the C.sub.max is selected from
the group consisting of at least about 10%, at least about 20%, at
least about 30%, at least about 40%, at least about 50%, at least
about 60%, at least about 70%, at least about 80%, at least about
90%, and at least about 100% greater than the C.sub.max exhibited
by a non-nanoparticulate formulation of nimesulide, administered at
the same dosage.
87. The method of claim 63, wherein the AUC of the nimesulide, when
assayed in the plasma of a mammalian subject following
administration, is greater than the AUC for a conventional,
non-nanoparticulate form of nimesulide, administered at the same
dosage.
88. The method of claim 87, wherein the AUC is selected from the
group consisting of at least about 10%, at least about 20%, at
least about 30%, at least about 40%, at least about 50%, at least
about 60%, at least about 70%, at least about 80%, at least about
90%, and at least about 100% greater than the AUC exhibited by a
non-nanoparticulate formulation of nimesulide, administered at the
same dosage.
89. The method of claim 63, additionally comprising administering
one or more non-nimesulide active agents.
90. The method of claim 63, additionally comprising administering
one or more non-nimesulide active agents effective for treating
fever, inflammation or pain.
91. The method of claim 89, wherein said non-nimesulide active
agent is selected from the group consisting of an analgesic, an
anti-inflammatory, an antipyretic, and a vasomodulator.
92. The method of claim 89, wherein said non-nimesulide active
agent is selected from the group consisting of nutraceuticals,
proteins, peptides, nucleotides, amino acids, anti-obesity drugs,
central nervous system stimulants, carotenoids, corticosteroids,
elastase inhibitors, anti-fungals, oncology therapies,
anti-emetics, analgesics, cardiovascular agents, anti-inflammatory
agents, NSAIDs, non-nimesulide COX-2 inhibitors, anthelmintics,
anti-arrhythmic agents, antibiotics, anticoagulants,
antidepressants, antidiabetic agents, antiepileptics,
antihistamines, antihypertensive agents, antimuscarinic agents,
antimycobacterial agents, antineoplastic agents,
immunosuppressants, antithyroid agents, antiviral agents,
anxiolytics, sedatives, astringents, alpha-adrenergic receptor
blocking agents, beta-adrenoceptor blocking agents, blood products
and substitutes, cardiac inotropic agents, contrast media,
corticosteroids, cough suppressants, diagnostic agents, diagnostic
imaging agents, diuretics, dopaminergics, haemostatics,
immunological agents, lipid regulating agents, muscle relaxants,
parasymPathomimetics, parathyroid calcitonin and biphosphonates,
prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergic
agents, stimulants and anoretics, symPathomimetics, thyroid agents,
vasodilators, vasomodulators, and xanthines.
93. The method of claim 63, wherein the subject is a human.
94. The method of claim 63, wherein the method is used to treat a
condition selected from the group consisting of rheumatic and joint
diseases, arthritis, rheumatoid arthritis, osteoarthritis,
periarthritis, tendonitis, bursitis, ankylosing spondylitis, joint
stiffness, lower back pain, gynecological conditions, menstrual
migraine attack, dysmenorrhoea, pelvic inflammatory disease,
urological conditions, urethritis, prostatitis, and vesiculitis
pyrexia, cardiovascular diseases, atherosclerosis, hypotension,
thrombophlebitis, arthrosis; inflammatory conditions, otitis,
rhinitis, sinusitis, pharyngitis, bronchitis nephrotoxicity,
mastitis, asthma, cancer, trauma, surgery, migraine headaches,
kidney disease, Alzheimer's disease, familial adenomatous
polyposis, diarrhea, colonic adenomas bone resorption, and related
conditions.
95. The method of claim 63, wherein the method is used to treat a
condition where anti-inflammatory agents, anti-angiogenesis agents,
antitumorigenic agents, immunosuppressive agents, NSAIDs, COX-2
inhibitors, analgesic agents, anti-thrombotic agents, narcotics, or
antifebrile agents are typically used.
Description
RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 10/276,400, filed on Jan. 15, 2003, which is a
continuation of U.S. application Ser. No. 09/572,961, filed on May
18, 2000, now U.S. Pat. No. 6,316,029.
FIELD OF THE INVENTION
[0002] The present invention relates to nanoparticulate
compositions comprising nimesulide. The nimesulide particles in
these compositions preferably have an effective average particle
size of less than about 2000 nm.
BACKGROUND OF THE INVENTION
[0003] I. Background Regarding Nanoparticulate Active Agent
Compositions
[0004] Nanoparticulate active agent compositions, first described
in U.S. Pat. No. 5,145,684 ("the '684 patent"), contain particles
of a poorly soluble therapeutic or diagnostic agent having adsorbed
onto, or associated with, the surface thereof a non-crosslinked
surface stabilizer. Such compositions provide superior
bioavailability, which can be affected by factors such as dosage
form and the dissolution rate of a drug. Poor bioavailability
constitutes a significant problem encountered in developing of
pharmaceutical compositions, particularly those containing an
active ingredient that is poorly soluble in water. By decreasing
the particle size of an active agent, the surface area of the
composition is increased, which generally results in increased
bioavailability. The '684 patent does not teach nanoparticulate
compositions of nimesulide.
[0005] Methods of making nanoparticulate active agent compositions
are described in, for example, U.S. Pat. Nos. 5,518,187 and
5,862,999, both for "Method of Grinding Pharmaceutical Substances;"
U.S. Pat. No. 5,718,388, for "Continuous Method of Grinding
Pharmaceutical Substances;" and U.S. Pat. No. 5,510,118 for
"Process of Preparing Therapeutic Compositions Containing
Nanoparticles."
[0006] Nanoparticulate active agent compositions are also
described, for example, in U.S. Pat. No. 5,298,262 for "Use of
Ionic Cloud Point Modifiers to Prevent Particle Aggregation During
Sterilization;" U.S. Pat. No. 5,302,401 for "Method to Reduce
Particle Size Growth During Lyophilization;" U.S. Pat. No.
5,318,767 for "X-Ray Contrast Compositions Useful in Medical
Imaging;" U.S. Pat. No. 5,326,552 for "Novel Formulation For
Nanoparticulate X-Ray Blood Pool Contrast Agents Using High
Molecular Weight Non-ionic Surfactants;" U.S. Pat. No. 5,328,404
for "Method of X-Ray Imaging Using Iodinated Aromatic
Propanedioates;" U.S. Pat. No. 5,336,507 for "Use of Charged
Phospholipids to Reduce Nanoparticle Aggregation;" U.S. Pat. No.
5,340,564 for "Formulations Comprising Olin 10-G to Prevent
Particle Aggregation and Increase Stability;" U.S. Pat. No.
5,346,702 for "Use of Non-Ionic Cloud Point Modifiers to Minimize
Nanoparticulate Aggregation During Sterilization;" U.S. Pat. No.
5,349,957 for "Preparation and Magnetic Properties of Very Small
Magnetic-Dextran Particles;" U.S. Pat. No. 5,352,459 for "Use of
Purified Surface Modifiers to Prevent Particle Aggregation During
Sterilization;" U.S. Pat. Nos. 5,399,363 and 5,494,683, both for
"Surface Modified Anticancer Nanoparticles;" U.S. Pat. No.
5,401,492 for "Water Insoluble Non-Magnetic Manganese Particles as
Magnetic Resonance Enhancement Agents;" U.S. Pat. No. 5,429,824 for
"Use of Tyloxapol as a Nanoparticulate Stabilizer;" U.S. Pat. No.
5,447,710 for "Method for Making Nanoparticulate X-Ray Blood Pool
Contrast Agents Using High Molecular Weight Non-ionic Surfactants;"
U.S. Pat. No. 5,451,393 for "X-Ray Contrast Compositions Useful in
Medical Imaging;" U.S. Pat. No. 5,466,440 for "Formulations of Oral
Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination
with Pharmaceutically Acceptable Clays;" U.S. Pat. No. 5,470,583
for "Method of Preparing Nanoparticle Compositions Containing
Charged Phospholipids to Reduce Aggregation;" U.S. Pat. No.
5,472,683 for "Nanoparticulate Diagnostic Mixed Carbamic Anhydrides
as X-Ray Contrast Agents for Blood Pool and Lymphatic System
Imaging;" U.S. Pat. No. 5,500,204 for "Nanoparticulate Diagnostic
Dimers as X-Ray Contrast Agents for Blood Pool and Lymphatic System
Imaging;" U.S. Pat. No. 5,518,738 for "Nanoparticulate NSAID
Formulations;" U.S. Pat. No. 5,521,218 for "Nanoparticulate
Iododipamide Derivatives for Use as X-Ray Contrast Agents;" U.S.
Pat. No. 5,525,328 for "Nanoparticulate Diagnostic Diatrizoxy Ester
X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;"
U.S. Pat. No. 5,543,133 for "Process of Preparing X-Ray Contrast
Compositions Containing Nanoparticles;" U.S. Pat. No. 5,552,160 for
"Surface Modified NSAID Nanoparticles;" U.S. Pat. No. 5,560,931 for
"Formulations of Compounds as Nanoparticulate Dispersions in
Digestible Oils or Fatty Acids;" U.S. Pat. No. 5,565,188 for
"Polyalkylene Block Copolymers as Surface Modifiers for
Nanoparticles;" U.S. Pat. No. 5,569,448 for "Sulfated Non-ionic
Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticle
Compositions;" U.S. Pat. No. 5,571,536 for "Formulations of
Compounds as Nanoparticulate Dispersions in Digestible Oils or
Fatty Acids;" U.S. Pat. No. 5,573,749 for "Nanoparticulate
Diagnostic Mixed Carboxylic Anydrides as X-Ray Contrast Agents for
Blood Pool and Lymphatic System Imaging;" U.S. Pat. No. 5,573,750
for "Diagnostic Imaging X-Ray Contrast Agents;" U.S. Pat. No.
5,573,783 for "Redispersible Nanoparticulate Film Matrices With
Protective Overcoats;" U.S. Pat. No. 5,580,579 for "Site-specific
Adhesion Within the GI Tract Using Nanoparticles Stabilized by High
Molecular Weight, Linear Poly(ethylene Oxide) Polymers;" U.S. Pat.
No. 5,585,108 for "Formulations of Oral Gastrointestinal
Therapeutic Agents in Combination with Pharmaceutically Acceptable
Clays;" U.S. Pat. No. 5,587,143 for "Butylene Oxide-Ethylene Oxide
Block Copolymers Surfactants as Stabilizer Coatings for
Nanoparticulate Compositions;" U.S. Pat. No. 5,591,456 for "Milled
Naproxen with Hydroxypropyl Cellulose as Dispersion Stabilizer;"
U.S. Pat. No. 5,593,657 for "Novel Barium Salt Formulations
Stabilized by Non-ionic and Anionic Stabilizers;" U.S. Pat. No.
5,622,938 for "Sugar Based Surfactant for Nanocrystals;" U.S. Pat.
No. 5,628,981 for "Improved Formulations of Oral Gastrointestinal
Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal
Therapeutic Agents;" U.S. Pat. No. 5,643,552 for "Nanoparticulate
Diagnostic Mixed Carbonic Anhydrides as X-Ray Contrast Agents for
Blood Pool and Lymphatic System Imaging;" U.S. Pat. No. 5,718,388
for "Continuous Method of Grinding Pharmaceutical Substances;" U.S.
Pat. No. 5,718,919 for "Nanoparticles Containing the R(-)Enantiomer
of Ibuprofen;" U.S. Pat. No. 5,747,001 for "Aerosols Containing
Beclomethasone Nanoparticle Dispersions;" U.S. Pat. No. 5,834,025
for "Reduction of Intravenously Administered Nanoparticulate
Formulation Induced Adverse Physiological Reactions;" U.S. Pat. No.
6,045,829 "Nanocrystalline Formulations of Human Immunodeficiency
Virus (HIV) Protease Inhibitors Using Cellulosic Surface
Stabilizers;" U.S. Pat. No. 6,068,858 for "Methods of Making
Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV)
Protease Inhibitors Using Cellulosic Surface Stabilizers;" U.S.
Pat. No. 6,153,225 for "Injectable Formulations of Nanoparticulate
Naproxen;" U.S. Pat. No. 6,165,506 for "New Solid Dose Form of
Nanoparticulate Naproxen;" U.S. Pat. No. 6,221,400 for "Methods of
Treating Mammals Using Nanocrystalline Formulations of Human
Immunodeficiency Virus (HIV) Protease Inhibitors;" U.S. Pat. No.
6,264,922 for "Nebulized Aerosols Containing Nanoparticle
Dispersions;" 6,267,989 for "Methods for Preventing Crystal Growth
and Particle Aggregation in Nanoparticle Compositions;" U.S. Pat.
No. 6,270,806 for "Use of PEG-Derivatized Lipids as Surface
Stabilizers for Nanoparticulate Compositions;" U.S. Pat. No.
6,316,029 for "Rapidly Disintegrating Solid Oral Dosage Form," U.S.
Pat. No. 6,375,986 for "Solid Dose Nanoparticulate Compositions
Comprising a Synergistic Combination of a Polymeric Surface
Stabilizer and Dioctyl Sodium Sulfosuccinate;" U.S. Pat. No.
6,428,814 for "Bioadhesive Nanoparticulate Compositions Having
Cationic Surface Stabilizers;" U.S. Pat. No. 6,431,478 for "Small
Scale Mill;" and 6,432,381 for "Methods for Targeting Drug Delivery
to the Upper and/or Lower Gastrointestinal Tract," all of which are
specifically incorporated by reference. In addition, U.S. Patent
Application No. 20020012675 A1, published on Jan. 31, 2002, for
"Controlled Release Nanoparticulate Compositions," and WO 02/098565
for "System and Method for Milling Materials," describe
nanoparticulate active agent compositions, and are specifically
incorporated by reference. None of these references describe
nanoparticulate nimesulide compositions.
[0007] Amorphous small particle compositions are described, for
example, in U.S. Pat. No. 4,783,484 for "Particulate Composition
and Use Thereof as Antimicrobial Agent;" U.S. Pat. No. 4,826,689
for "Method for Making Uniformly Sized Particles from
Water-Insoluble Organic Compounds;" U.S. Pat. No. 4,997,454 for
"Method for Making Uniformly-Sized Particles From Insoluble
Compounds;" U.S. Pat. No. 5,741,522 for "Ultrasmall, Non-aggregated
Porous Particles of Uniform Size for Entrapping Gas Bubbles Within
and Methods;" and 5,776,496, for "Ultrasmall Porous Particles for
Enhancing Ultrasound Back Scatter."
[0008] II. Background Regarding Nimesulide
[0009] Nimesulide, also known as
N-(4-Nitro-2-phenoxy-phenyl)-methanesulfo- namide, is a
non-steroidal anti-inflammatory drug (NSAID) having the following
structure: 1
[0010] Nimesulide has a molecular weight of 308.31 g/mol and is
practically insoluble in water, having a half-life of about 4
hours. It operates by selectively inhibiting cyclooxygenase-2
(COX-2).
[0011] Therapeutic concentrations of nimesulide cause several
actions, including the following: (a) inhibition of prostaglandin
synthesis, (b) inhibition of toxic oxygen metabolite formation, (c)
inhibition of cytokine release, (d) inhibition of histamine
release, and (e) inhibition of cartilage degradation. In accord
with these actions, nimesulide exerts anti-inflammatory, analgesic
and anti-pyretic activities, and therefore effectively treats a
wide range of disorders.
[0012] One drawback of nimesulide is that it can be difficult to
administer, due to its near insolubility in water. The art has
addressed several ways to render nimesulide more bioavailable. U.S.
Pat. No. 5,756,546 to Pirotte et al. discloses a water-soluble salt
formed from equimolar amounts of nimesulide and L-lysine, but the
salt can be contaminated with excess L-lysine or insoluble
nimesulide upon any variation from the 1:1 molar ratio. U.S. Pat.
No. 5,744,165 Geczy et al. relates to alkali and alkaline earth
salts of nimesulide that, when combined with a cyclodextrin to form
inclusion complexes, can be dissolved in water. However,
compositions of this type can deliver unwanted amounts of
cyclodextrin and sodium ion to a patient. U.S. Pat. No. 6,194,462
to Giorgetti discloses soluble formulations of nimesulide achieved
by dissolving the drug in a mixture of water at basic pH and one or
more alcohols such as ethanol. In contrast, U.S. Pat. No. 6,288,121
to Bader et al. discloses emulsions of nimesulide in liquid crystal
form for the controlled release of the drug, while U.S. Pat. No.
5,998,480 to Giorgetti relates to bioavailable formulations of
nimesulide, a phospholipid, and an organic or inorganic acid.
[0013] Nimesulide has been marketed under numerous trade names,
including Ainex.RTM., Aulin.RTM., Donulide.RTM., Edrigyl.RTM.,
Eskaflam.RTM., Fansidol.RTM., Flogovital.RTM., Guaxan.RTM.,
Heugan.RTM., Mesulid.RTM., Nemil.RTM., Nexen.RTM., Nide.RTM.,
Nidol.RTM., Nimed.RTM., Nimedex.RTM., Nisulid.RTM., Plarium.RTM.,
Scaflam.RTM., Scaflan.RTM., and Sulidene.RTM..
[0014] There is a need in the art for nimesulide compositions which
can decrease frequency of dosing, improve clinical efficacy, and
potentially reduce side effects. The present invention satisfies
these needs.
SUMMARY OF THE INVENTION
[0015] The present invention provides nanoparticulate nimesulide
compositions. The compositions preferably comprise nimesulide and
at least one surface stabilizer adsorbed on or associated with the
surface of the nimesulide particles. The nanoparticulate nimesulide
particles preferably have an effective average particle size of
less than about 2000 nm.
[0016] The invention also provides pharmaceutical compositions that
comprise nanoparticulate nimesulide. The pharmaceutical
compositions preferably comprise nimesulide, at least one surface
stabilizer, and at least one pharmaceutically acceptable carrier,
as well as any desired excipients known to those in the art. The
compositions can be formulated into any desired dosage form.
[0017] In another aspect, the invention includes nanoparticulate
nimesulide compositions having improved pharmacokinetic profiles,
such as improved T.sub.max, C.sub.max, and AUC parameters, relative
to conventional solubilized, microcrystalline or
non-nanoparticulate nimesulide formulations.
[0018] In yet another aspect, the invention encompasses a
nimesulide composition having a pharmacokinetic profile that is not
substantially affected by the fed or fasted state of a subject
ingesting the composition, preferably as defined by C.sub.max and
AUC guidelines given by the U.S. Food and Drug Administration
and/or the corresponding European regulatory agency (EMEA).
[0019] Other aspects of the invention include, but are not limited
to, nanoparticulate nimesulide compositions that, as compared to
conventional non-nanoparticulate formulations of nimesulide,
preferably have one or more of the following properties: (1)
smaller dosage form size; (2) smaller doses of drug required to
obtain the same pharmacological effect; (3) increased
bioavailability; (4) an increased rate of dissolution for the
nanoparticulate nimesulide compositions; and (5) bioadhesive
nimesulide compositions.
[0020] This invention further discloses methods of making a
nanoparticulate nimesulide composition. The methods comprise
contacting nimesulide and at least one surface stabilizer for a
time and under conditions sufficient to provide a nanoparticulate
nimesulide composition. The one or more surface stabilizers can be
contacted with nimesulide before, preferably during, or after size
reduction of the nimesulide.
[0021] The present invention also includes methods of using
nanoparticulate nimesulide compositions for treating a wide range
of conditions and disorders mediated by COX-2, including, but not
limited to, disorders characterized by inflammation, pain, and/or
fever. Thus, compositions of the invention are useful for
indications where anti-inflammatory agents, anti-angiogenesis
agents, antitumorigenic agents, immunosuppressive agents, NSAIDs,
COX-2 inhibitors, analgesic agents, anti-thrombotic agents,
narcotic or antifebrile agents are typically used.
[0022] The methods comprise administering to a subject a
therapeutically effective amount of a nanoparticulate nimesulide
pharmaceutical composition according to the invention.
Additionally, a subject may be administered a therapeutic amount of
a pharmaceutical composition that comprises both nanoparticulate
nimesulide and non-nanoparticulate nimesulide. Alternatively, the
methods comprise administering to a subject a therapeutically
effective amount of a nanoparticulate nimesulide composition in
combination with one or more non-nimesulide active agents.
[0023] Both the foregoing general description and the following
detailed description are exemplary and explanatory, and are
intended to provide further explanation of the invention as
claimed. Other objects, advantages, and novel features will be
readily apparent to those skilled in the art from the following
detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0024] The present invention relates to nanoparticulate nimesulide
compositions. The compositions preferably comprise nimesulide and
at least one surface stabilizer adsorbed on or associated with the
surface of the nimesulide particles. The nanoparticulate nimesulide
particles preferably have an effective average particle size of
less than about 2000 nm.
[0025] The present invention also relates to pharmaceutical
compositions that comprise a nanoparticulate nimesulide active
agent. The pharmaceutical compositions preferably comprise
nimesulide, at least one surface stabilizer, and at least one
pharmaceutically acceptable carrier. Non-toxic physiologically
acceptable carriers, adjuvants, and vehicles are collectively
referred to as carriers herein.
[0026] The pharmaceutical compositions may be formulated for
parenteral injection, including intravenous, intramuscular, or
subcutaneous; oral administration in solid, liquid, or aerosol
form; or vaginal, nasal, rectal, ocular, local (such as in powders,
ointments or drops), buccal, intracisternal, intraperitoneal, or
topical administration, and the like.
[0027] Solid dosage forms are preferred, though any
pharmaceutically acceptable dosage form may be employed. Exemplary
solid dosage forms include, but are not limited to, tablets,
capsules, sachets, lozenges, powders, pills, or granules. A solid
dosage form may be, for example, a fast melt dosage form,
controlled release dosage form, lyophilized dosage form, delayed
release dosage form, extended release dosage form, pulsatile
release dosage form, mixed immediate release and controlled release
dosage form, or a combination thereof. Solid dose tablet
formulations are preferred.
[0028] I. Technical Challenges Overcome by the Inventors
[0029] As taught in the '684 patent, not every combination of
surface stabilizer and active agent will result in a stable
nanoparticulate composition. Thus, the discovery that stable
nanoparticulate nimesulide formulations can be made was
surprising.
[0030] In general, the rate of dissolution of a particulate drug
increases with increasing surface area, e.g., decreasing particle
size. Consequently, methods of making finely divided drugs have
been studied and efforts have been made to control the size and
size range of drug particles in pharmaceutical compositions.
Nanoparticulate active agent formulations suitable for
administration as pharmaceuticals require formulation of the active
ingredient into a colloidal dispersion that exhibits the acceptable
nanoparticle size range and the stability to maintain such size
range without agglomerating. Thus, merely increasing surface area
by decreasing particle size does not assure success. Further
challenges include forming solid dose forms that are redispersible
into nanoparticle form upon administration to a patient, to
maintain the benefit of nanoparticle nimesulide over a traditional
microparticulate or solubilized nimesulide dosage form.
[0031] II. Summary of Advantages of Nanoparticulate Nimesulide
Formulations
[0032] Advantages of nanoparticulate nimesulide formulations,
relative to conventional non-nanoparticulate or solubilized
formulations of nimesulide include, but are not limited to: (1)
faster onset of action; (2) a potential decrease in the frequency
of dosing; (3) smaller tablet (or other solid dosage form) size or
liquid dose volumes; (4) smaller doses of drug required to obtain
the same pharmacological effect; (5) increased bioavailability; (6)
an increased rate of dissolution; (7) high redispersibility of the
nanoparticulate nimesulide particles present in the compositions of
the invention following administration; (8) improved performance
characteristics for oral, intravenous, subcutaneous, or
intramuscular injection, such as higher dose loading; (9) improved
pharmacokinetic profiles, such as improved T.sub.max, C.sub.max,
and AUC profiles; (10) substantially similar or bioequivalent
pharmacokinetic profiles of the nanoparticulate nimesulide
compositions when administered in the fed versus the fasted state;
(11) bioadhesive nimesulide compositions; (12) low viscosity liquid
nanoparticulate nimesulide dosage forms can be made; (13) for
liquid nanoparticulate nimesulide compositions having a low
viscosity--better subject compliance due to the perception of a
lighter formulation which is easier to consume and digest; (14) for
liquid nanoparticulate nimesulide compositions having a low
viscosity--ease of dispensing because one can use a cup or a
syringe; (15) the nanoparticulate nimesulide compositions can be
sterile filtered; (16) the nanoparticulate nimesulide compositions
can be used in conjunction with other active agents; (17) the
nanoparticulate nimesulide compositions are suitable for parenteral
administration; and (18) the nanoparticulate nimesulide
compositions do not require organic solvents or pH extremes.
[0033] Moreover, nanoparticulate nimesulide formulations do not
possess the sedative and addictive properties of narcotic
analgesics. Because nimesulide does not cause drowsiness and is not
addictive, it is a preferred analgesic when ambulation is important
or when treatment is protracted and chemical dependency could
result from prolonged use of narcotic analgesics.
[0034] III. Definitions
[0035] The present invention is described herein using several
definitions that are set forth below and throughout the
specification.
[0036] "About" will be understood by persons of ordinary skill in
the art and will vary to some extent on the context in which the
term is used. If there are uses of the term that are not clear to
persons of ordinary skill in the art given the context in which it
is used, "about" will mean up to plus or minus 10% of the
particular term.
[0037] "Conventional" or "non-nanoparticulate active agent" means
an active agent that is solubilized or that has an effective
average particle size of greater than about 2 microns. "Effective
average particle size of greater than about 2 microns" means that
at least 50% of the particles of the composition have a size of
greater than about 2 microns.
[0038] "Pharmaceutically acceptable" as used herein refers to those
compounds, materials, compositions, and/or dosage forms which are,
within the scope of sound medical judgment, suitable for use in
contact with the tissues of human beings and animals without
excessive toxicity, irritation, allergic response, or other problem
or complication, commensurate with a reasonable benefit/risk
ratio.
[0039] "Pharmaceutically acceptable salts" as used herein refers to
derivatives wherein the parent compound is modified by making acid
or base salts thereof. Examples of pharmaceutically acceptable
salts include, but are not limited to, mineral or organic acid
salts of basic residues such as amines; alkali or organic salts of
acidic residues such as carboxylic acids; and the like. The
pharmaceutically acceptable salts include the conventional
non-toxic salts or the quaternary ammonium salts of the parent
compound formed, for example, from non-toxic inorganic or organic
acids. For example, such conventional non-toxic salts include those
derived from inorganic acids such as hydrochloric, hydrobromic,
sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts
prepared from organic acids such as acetic, propionic, succinic,
glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,
pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,
salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isethionic, and the
like.
[0040] "Poorly water soluble drugs" as used herein means drugs
having a solubility of less than about 30 mg/ml, preferably less
than about 20 mg/ml, preferably less than about 10 mg/ml, or
preferably less than about 1 mg/ml. Such drugs tend to be
eliminated from the gastrointestinal tract before being absorbed
into the circulation. Moreover, poorly water soluble drugs tend to
be unsafe for intravenous administration techniques, which are used
primarily in conjunction with highly water soluble drug
substances.
[0041] As used herein with reference to stable nimesulide
particles, "stable" includes, but is not limited to, one or more of
the following parameters: (1) that the nimesulide particles do not
appreciably flocculate or agglomerate due to interparticle
attractive forces, or otherwise significantly increase in particle
size over time; (2) that the physical structure of the nimesulide
particles is not altered over time, such as by conversion from an
amorphous phase to crystalline phase; (3) that the nimesulide
particles are chemically stable; and/or (4) where the nimesulide
has not been subject to a heating step at or above the melting
point of the nimesulide in the preparation of the nanoparticles of
the invention.
[0042] "Therapeutically effective amount" as used herein with
respect to a drug dosage, means a dosage that provides the specific
pharmacological response for which the drug is administered in a
significant number of subjects in need of such treatment. A
"therapeutically effective amount," administered to a particular
subject in a particular instance, will not always effectively treat
the diseases described herein, even though such dosage is deemed a
"therapeutically effective amount" by those skilled in the art.
Throughout this description, drug dosages are, in particular
instances, measured as oral dosages, or with reference to drug
levels as measured in blood.
[0043] IV. Preferred Characteristics of Nanoparticulate Nimesulide
Compositions
[0044] A. Fast Onset of Activity
[0045] Of particular importance, conventional formulations of
nimesulide are inappropriate for managing acute pain due to delayed
onset of action, as conventional nimesulide formulations have a
T.sub.max of 4-6 hours, which is more than five times as long as
most narcotic analgesic drugs. See The Physician 's Desk Reference,
56.sup.th Ed., pp. 446 and 1054. Unlike conventional nimesulide
formulations, nanoparticulate nimesulide formulations, which
exhibit faster onset of action, are useful for treating acute pain
where fast pain relief is required.
[0046] B. Increased Bioavailability and Lower Dosages
[0047] Relative to conventional nimesulide formulations, the
inventive nanoparticulate nimesulide compositions preferably
exhibit increased bioavailability, require smaller doses, and show
longer plasma half-life.
[0048] As another advantage, nanoparticulate formulations of
nimesulide also provide a longer duration of pain relief relative
to traditional narcotic analgesic drugs. While traditional
narcotics provide fast onset of action, the duration of pain relief
is short. Nanoparticulate nimesulide formulations combine the fast
onset of traditional narcotics with the duration of pain relief of
conventional NSAIDs. The long half-life of nimesulide,
approximately 20 hours as compared to 2-3 hours for most narcotics,
confers a long duration of action and thus requires less frequent
dosing.
[0049] Enhanced bioavailability enables the use of lower doses,
which also results in decreased toxicity associated with
nimesulide. In this regard, lower doses of nanoparticulate
nimesulide can achieve the same or better therapeutic effects as
larger doses of conventional nimesulide. Such lower doses can be
realized due to the greater bioavailability of nanoparticulate drug
formulations as compared to conventional drug formulations.
Nimesulide, like any drug, can have adverse side effects.
Therefore, the ability to administer lower doses of it translates
into fewer adverse side effects.
[0050] Enhanced bioavailability also can enable the use of a
smaller dosage size. This is significant for certain patient
populations, such as the elderly, juvenile and infant.
[0051] C. Improved Pharmacokinetic Profiles
[0052] The inventive nanoparticulate nimesulide compositions also
preferably exhibit a desirable pharmacokinetic profile when
administered to mammalian subjects. The desirable pharmacokinetic
profile preferably includes, but is not limited to: (1) that the
T.sub.max of nimesulide, when assayed in the plasma of a mammalian
subject following administration, is preferably less than the
T.sub.max for a conventional, non-nanoparticulate form of
nimesulide administered at the same dosage; (2) that the C.sub.max
of nimesulide, when assayed in the plasma of a mammalian subject
following administration, is preferably greater than the C.sub.max
for a conventional, non-nanoparticulate form of nimesulide
administered at the same dosage; and/or (3) that the AUC of
nimesulide, when assayed in the plasma of a mammalian subject
following administration, is preferably greater than the AUC for a
conventional, non-nanoparticulate form of nimesulide administered
at the same dosage.
[0053] The desirable pharmacokinetic profile, as used herein, is
the pharmacokinetic profile measured after an initial dose of
nimesulide. The dose can be formulated in any way as described
below and as known to those skilled in the art.
[0054] A preferred nanoparticulate nimesulide composition exhibits,
in comparative pharmacokinetic testing with a non-nanoparticulate
formulation of nimesulide administered at the same dosage, a
T.sub.max not greater than about 90%, not greater than about 80%,
not greater than about 70%, not greater than about 60%, not greater
than about 50%, not greater than about 30%, not greater than about
25%, not greater than about 20%, not greater than about 15%, or not
greater than about 10% of the T.sub.max, exhibited by the
non-nanoparticulate formulation of nimesulide.
[0055] A preferred nanoparticulate nimesulide composition exhibits,
in comparative pharmacokinetic testing with a non-nanoparticulate
formulation of nimesulide administered at the same dosage, a
C.sub.max that is at least about 10%, at least about 20%, at least
about 30%, at least about 40%, at least about 50%, at least about
60%, at least about 70%, at least about 80%, at least about 90%, or
at least about 100% greater than the C.sub.max exhibited by the
non-nanoparticulate formulation of nimesulide.
[0056] A preferred nanoparticulate nimesulide composition exhibits,
in comparative pharmacokinetic testing with a non-nanoparticulate
formulation of nimesulide administered at the same dosage, an AUC
that is at least about 10%, at least about 20%, at least about 30%,
at least about 40%, at least about 50%, at least about 60%, at
least about 70%, at least about 80%, at least about 90%, or at
least about 100% greater than the AUC exhibited by the
non-nanoparticulate formulation of nimesulide.
[0057] According to the invention, any formulation that provides
the desired pharmacokinetic profile is suitable for administration.
Exemplary types of formulations that give such profiles are liquid
dispersions, gels, aerosols, ointments, creams and solid dose
forms.
[0058] D. The Pharmacokinetic Profiles are not Affected by the Fed
or Fasted State of the Subject Ingesting the Compositions
[0059] Certain drugs have been shown to have significantly lower
plasma levels when administered under fasting conditions as when
administered immediately after a standard test meal. This
significant difference is undesirable.
[0060] Nanoparticulate nimesulide formulations of the invention
preferably alleviate this problem. That is, they preferably reduce
the differences in, or more preferably do not produce significantly
different, absorption levels when administered under fed as
compared to fasting conditions.
[0061] Thus, the invention encompasses a nimesulide composition
having a pharmacokinetic profile that is not substantially affected
by the fed or fasted state of a subject ingesting the composition.
This means that there is no substantial difference in the quantity
of drug absorbed or the rate of drug absorption when the
nanoparticulate nimesulide compositions are administered in the fed
versus the fasted state.
[0062] The invention also encompasses a nimesulide composition for
which administration to a subject in a fasted state is
bioequivalent to administration to a subject in a fed state.
"Bioequivalency" is preferably established by a 90% Confidence
Interval (CI) of between 0.80 and 1.25 for both C.sub.max and AUC
under U.S. Food and Drug Administration regulatory guidelines, or a
90% CI for AUC of between 0.80 to 1.25 and a 90% CI for C.sub.max
of between 0.70 to 1.43 under the European EMEA regulatory
guidelines (T.sub.max is not relevant for bioequivalency
determinations under USFDA and EMEA regulatory guidelines).
[0063] Benefits of a dosage form that substantially eliminates the
effect of food include an increase in convenience, which increases
patient compliance, as a patient does not need to ensure that they
are taking a dose either with or without food. This is significant,
as poor patient compliance can defeat the purpose of administering
a drug.
[0064] The difference in absorption of the inventive nimesulide
compositions, when administered in a fed versus a fasted state,
preferably is less than about 100%, less than about 90%, less than
about 80%, less than about 70%, less than about 60%, less than
about 50%, less than about 40%, less than about 30%, less than
about 25%, less than about 20%, less than about 15%, less than
about 10%, less than about 5%, or less than about 3%.
[0065] E. Rapid Dissolution Profiles
[0066] Nanoparticulate nimesulide compositions of the invention
preferably have rapid dissolution profiles. Rapid dissolution of an
administered active agent is desirable, as faster dissolution
generally leads to faster onset of action and greater
bioavailability. To maximize the dissolution profile and
bioavailability of nimesulide, it would be useful to increase the
drug's dissolution so that it could attain a level close to
100%.
[0067] The inventive nimesulide compositions preferably have a
dissolution profile in which at least about 20% of the composition
is dissolved within 5 minutes. In other embodiments, at least about
30% or about 40% of the nimesulide composition is dissolved within
about 5 minutes. In yet other embodiments, preferably at least
about 40%, about 50%, about 60%, about 70%, or about 80% of the
nimesulide composition is dissolved within about 10 minutes.
Finally, in another embodiment, preferably at least about 70%,
about 80%, about 90%, or about 100% of the nimesulide composition
is dissolved within about 20 minutes.
[0068] Dissolution is preferably measured in a medium that is
discriminating. Such a dissolution medium will produce two
different dissolution curves for two products having different
dissolution profiles in gastric juices; i.e., the dissolution
medium is predictive of in vivo dissolution of a composition. An
exemplary dissolution medium is an aqueous medium containing the
surfactant sodium lauryl sulfate at 0.025 M. Determination of the
amount dissolved can be performed by spectrophotometry. The
rotating blade method (European Pharmacopoeia) can be used to
measure dissolution.
[0069] F. Redispersion of Nanoparticulate Nimesulide Dosage Forms
to Nanoparticulate Particle Size
[0070] The inventive nanoparticulate nimesulide compositions
preferably redisperse such that the effective average particle size
of the redispersed nimesulide particles is less than about 2
microns. This is significant because if, upon administration, the
nanoparticulate nimesulide compositions did not redisperse to a
substantially nanoparticulate particle size, then the dosage form
might lose the benefits of a nanoparticulate formulation.
[0071] This is because nanoparticulate active agent compositions
benefit from the small particle size of the active agent. If the
active agent does not redisperse into small particle sizes upon
administration, then "clumps" or agglomerated active agent
particles are formed, owing to the extremely high surface free
energy of the nanoparticulate system and the thermodynamic driving
force to achieve an overall reduction in free energy. With the
formation of such agglomerated particles, the bioavailability of
the dosage form may fall well below that observed with a liquid
dispersion form of the nanoparticulate active agent.
[0072] Moreover, the inventive nanoparticulate nimesulide
compositions preferably exhibit dramatic redispersion upon
administration to a mammal, such as a human or animal. This can be
demonstrated by reconstitution/redispersion in a biorelevant
aqueous medium such that the effective average particle size of the
redispersed nimesulide particles is less than about 2 microns.
Biorelevant aqueous media include any aqueous media that exhibit
representative ionic strength and pH. The desired pH and ionic
strength is one that represents physiological conditions found in
the human body. Such biorelevant aqueous media can be, for example,
aqueous electrolyte solutions or aqueous solutions of any salt,
acid, base, or a combination thereof.
[0073] Biorelevant pH is well known in the art. For example, in the
stomach, the pH ranges from slightly less than 2 (but typically
greater than 1) up to 4 or 5. In the small intestine the pH can
range from 4 to 6, and in the colon it can range from 6 to 8.
Biorelevant ionic strength is also well known in the art. Fasted
state gastric fluid has an ionic strength of about 0.1 M, while
fasted state intestinal fluid has an ionic strength of about 0.14.
See e.g., Lindahl et al., "Characterization of Fluids from the
Stomach and Proximal Jejunum in Men and Women," Pharm. Res., 14
(4): 497-502 (1997).
[0074] It is believed that the pH and ionic strength of a test
solution are more critical than the specific chemical content.
Accordingly, appropriate pH and ionic strength values can be
obtained through numerous combinations of strong acids, strong
bases, salts, single or multiple conjugate acid-base pairs (i.e.,
weak acids and corresponding salts of that acid), monoprotic and
polyprotic electrolytes, etc.
[0075] Representative electrolyte solutions can be, but are not
limited to, HCl solutions, ranging in concentration from about
0.001 to about 0.1 M, and NaCl solutions, ranging in concentration
from about 0.001 to about 0.1 M, and mixtures thereof. For example,
electrolyte solutions can be, but are not limited to, about 0.1 M
HCl or less, about 0.01 M HCl or less, about 0.001 M HCl or less,
about 0.1 M NaCl or less, about 0.01 M NaCl or less, about 0.001 M
NaCl or less, and mixtures thereof. Of these electrolyte solutions,
0.01 M HCl and/or 0.1 M NaCl, are most representative of fasted
human physiological conditions, owing to the pH and ionic strength
conditions of the proximal gastrointestinal tract.
[0076] Electrolyte concentrations of 0.001 M HCl, 0.01 M HCl, and
0.1 M HCl correspond to pH 3, pH 2, and pH 1, respectively. Thus, a
0.01 M HCl solution simulates typical acidic conditions found in
the stomach. A solution of 0.1 M NaCl provides a reasonable
approximation of the ionic strength conditions found throughout the
body, including the gastrointestinal fluids, although
concentrations higher than 0.1 M may be employed to simulate fed
conditions within the human GI tract.
[0077] Exemplary solutions of salts, acids, bases or combinations
thereof, that exhibit the desired pH and ionic strength include,
but are not limited to, phosphoric acid/phosphate salts+sodium,
potassium and calcium salts of chloride, acetic acid/acetate
salts+sodium, potassium and calcium salts of chloride, carbonic
acid/bicarbonate salts+sodium, potassium and calcium salts of
chloride, and citric acid/citrate salts+sodium, potassium and
calcium salts of chloride.
[0078] In other embodiments of the invention, the redispersed
nimesulide particles (redispersed in an aqueous, biorelevant, or
any other suitable media) have an effective average particle size
of less than about 1900 nm, less than about 1800 nm, less than
about 1700 nm, less than about 1600 nm, less than about 1500 nm,
less than about 1400 nm, less than about 1300 nm, less than about
1200 nm, less than about 1100 nm, less than about 1000 nm, less
than about 900 nm, less than about 800 nm, less than about 700 nm,
less than about 600 nm, less than about 500 nm, less than about 400
nm, less than about 300 nm, less than about 250 nm, less than about
200 nm, less than about 150 nm, less than about 100 nm, less than
about 75 nm, or less than about 50 nm, as measured by
light-scattering methods, microscopy, or other appropriate
methods.
[0079] By "an effective average particle size of less than about
2000 nm" it is meant that at least 50% of the nimesulide particles
have a particle size less than the effective average, by weight,
i.e., less than about 2000 nm, 1900 nm, 1800 nm, etc., when
measured by the above-noted techniques. Preferably, at least about
70%, about 90%, about 95%, or about 99% of the nimesulide particles
have a particle size less than the effective average, i.e., less
than about 2000 nm, 1900 nm, 1800 nm, 1700 nm, etc.
[0080] Redispersibility can be tested using any suitable means
known in the art. See e.g., the example sections of U.S. Pat. No.
6,375,986 for "Solid Dose Nanoparticulate Compositions Comprising a
Synergistic Combination of a Polymeric Surface Stabilizer and
Dioctyl Sodium Sulfosuccinate."
[0081] G. Bioadhesive Nanoparticulate Nimesulide Compositions
[0082] Nanoparticulate nimesulide compositions of the invention can
exhibit bioadhesive properties. Such compositions comprise one or
more cationic surface stabilizers, which are described in more
detail below.
[0083] The term bioadhesion refers to any attractive interaction
between two biological surfaces or between a biological and a
synthetic surface. In the case of bioadhesive nanoparticulate
nimesulide compositions, the term bioadhesion describes the
adhesion between nanoparticulate nimesulide compositions and a
biological substrate (e.g., gastrointestinal mucin, lung tissue,
nasal mucosa, etc.). See, e.g., U.S. Pat. No. 6,428,814 for
"Bioadhesive Nanoparticulate Compositions Having Cationic Surface
Stabilizers," which is specifically incorporated by reference.
Bioadhesive formulations of nimesulide exhibit exceptional
bioadhesion to biological substrates.
[0084] Bioadhesive nimesulide compositions are useful in any
situation where it is desirable to apply the compositions to a
biological surface. Bioadhesive nimesulide compositions coat the
targeted surface in a continuous and uniform film, which is
invisible to the naked human eye.
[0085] Bioadhesion slows transit of a nimesulide composition, and
some nimesulide particles inevitably adhere to tissue other than
the mucous cells. This provides a prolonged exposure to nimesulide,
thereby increasing absorption and bioavailability of the
administered dosage.
[0086] H. Low Viscosity Liquid Nanoparticulate Nimesulide
Compositions
[0087] A liquid dosage form of a conventional microcrystalline or
non-nanoparticulate or solubilized nimesulide composition would be
expected to be a relatively large volume, highly viscous substance
which would not be well accepted by patient populations. This is
significant, as liquid dosage forms can be particularly useful for
patient populations such as the elderly and infant.
[0088] Liquid dosage forms of the nanoparticulate nimesulide
compositions of the invention provide significant advantages over a
liquid dosage form of a conventional microcrystalline or
solubilized nimesulide composition. The low viscosity and silky
texture of liquid dosage forms of the nanoparticulate nimesulide
compositions of the invention result in advantages in both
preparation and use. These advantages include, for example: (1)
better subject compliance due to the perception of a lighter
formulation which is easier to injest; (2) ease of dispensing as
compared to a highly viscous formulation; (3) potential for
formulating a higher concentration of nimesulide resulting in a
smaller dosage volume and thus less volume for the subject to
consume; and (4) easier overall formulation concerns.
[0089] The viscosities of liquid dosage forms of nanoparticulate
nimesulide according to the invention are preferably less than
about {fraction (1/200)}, less than about {fraction (1/175)}, less
than about {fraction (1/150)}, less than about {fraction (1/125)},
less than about {fraction (1/100)}, less than about {fraction
(1/75)}, less than about {fraction (1/50)}, or less than about
{fraction (1/25)} of a topical liquid dosage form of a
non-nanoparticulate nimesulide composition, at about the same
concentration per ml of nimesulide.
[0090] Typically the viscosity of liquid nanoparticulate nimesulide
dosage forms of the invention, at a shear rate of 0.1 (1/s) and
measured at 20.degree. C., is from about 2000 mPa.multidot.s to
about 1 mPa.multidot.s, from about 1900 mPa.multidot.s to about 1
mPa.multidot.s, from about 1800 mPa.multidot.s to about 1
mPa.multidot.s, from about 1700 mPa.multidot.s to about 1
mPa.multidot.s, from about 1600 mPa.multidot.s to about 1
mPa.multidot.s, from about 1500 mPa.multidot.s to about 1
mPa.multidot.s, from about 1400 mPa.multidot.s to about 1
mPa.multidot.s, from about 1300 mPa.multidot.s to about 1
mPa.multidot.s, from about 1200 mPa.multidot.s to about 1
mPa.multidot.s, from about 1100 mPa.multidot.s to about 1
mPa.multidot.s, from about 1000 mPa.multidot.s to about 1
mPa.multidot.s, from about 900 mPa.multidot.s to about 1
mPa.multidot.s, from about 800 mPa.multidot.s to about 1
mPa.multidot.s, from about 700 mPa.multidot.s to about 1
mPa.multidot.s, from about 600 mPa.multidot.s to about 1
mPa.multidot.s, from about 500 mPa.multidot.s to about 1
mPa.multidot.s, from about 400 mPa.multidot.s to about 1
mPa.multidot.s, from about 300 mPa.multidot.s to about 1
mPa.multidot.s, from about 200 mPa.multidot.s to about 1
mPa.multidot.s, from about 175 mPa.multidot.s to about 1
mPa.multidot.s, from about 150 mPa.multidot.s to about 1
mPa.multidot.s, from about 125 mPa.multidot.s to about 1
mPa.multidot.s, from about 100 mPa.multidot.s to about 1
mPa.multidot.s, from about 75 mPa.multidot.s to about 1
mPa.multidot.s, from about 50 mPa.multidot.s to about 1
mPa.multidot.s, from about 25 mPa.multidot.s to about 1
mPa.multidot.s, from about 15 mPa.multidot.s to about 1
mPa.multidot.s, from about 10 mPa.multidot.s to about 1
mPa.multidot.s, or from about 5 mPa.multidot.s to about 1
mPa.multidot.s.
[0091] Viscosity is concentration and temperature dependent.
Typically, a higher concentration results in a higher viscosity,
while a higher temperature results in a lower viscosity. Viscosity
as defined above refers to measurements taken at about 20.degree.
C. (The viscosity of water at 20.degree. C. is 1 mPa.multidot.s.)
The invention encompasses equivalent viscosities measured at
different temperatures.
[0092] The liquid formulations of this invention can be formulated
for dosages in any volume but preferably equivalent or smaller
volumes than a liquid dosage form of a non-nanoparticulate or
solubilized nimesulide composition.
[0093] I. Sterile Filtered Nanoparticulate Nimesulide
Compositions
[0094] The nanoparticulate nimesulide compositions of the invention
can be sterile filtered. This obviates the need for heat
sterilization, which can harm or degrade nimesulide, as well as
result in crystal growth and particle aggregation.
[0095] Sterile filtration can be difficult because of the required
small particle size of the composition. Filtration is an effective
method for sterilizing homogeneous solutions when the membrane
filter pore size is less than or equal to about 0.2 microns (200
nm) because a 0.2 micron filter is sufficient to remove essentially
all bacteria. Sterile filtration is normally not used to sterilize
suspensions of micron-sized nimesulide because the nimesulide
particles are too large to pass through the membrane pores.
[0096] A sterile nanoparticulate nimesulide dosage form is
particularly useful in treating immunocompromised patients, infants
or juvenile patients, and the elderly, as these patient groups are
the most susceptible to infection caused by a non-sterile liquid
dosage form.
[0097] Because the nanoparticulate nimesulide compositions of the
invention, formulated into a liquid dosage form, can be sterile
filtered, and because the compositions can have a very small
nimesulide effective average particle size, the compositions are
suitable for parenteral administration.
[0098] J. Combination Pharmacokinetic Profile Compositions
[0099] In one embodiment of the invention, a first nimesulide
formulation providing the pharmacokinetic profile described above
is co-administered with at least one other nimesulide formulation
that generates a different pharmacokinetic profile, specifically
one exhibiting slower absorption into the bloodstream, and
therefore a longer T.sub.max and typically a lower C.sub.max. For
example, the second nimesulide formulation can have a conventional
particle size, which produces a longer T.sub.max, and typically a
lower C.sub.max. Alternatively, a second, third or fourth
nimesulide formulation can differ from the first, and from each
other, in the effective average particle sizes of each composition.
The difference particle sizes produce different T.sub.max values.
The combination of fast pain relief provided by the first
formulation and longer-lasting pain relief provided by the second
(or third, fourth, etc.) formulation can reduce the dose frequency
required.
[0100] If the second nimesulide composition has a nanoparticulate
particle size, then preferably the nimesulide particles of the
second composition have at least one surface stabilizer associated
with the surface of the drug particles. The one or more surface
stabilizers can be the same as or different from the surface
stabilizer(s) present in the first nimesulide composition.
[0101] Preferably where co-administration of a "fast-acting"
formulation and a "longer-lasting" formulation is desired, the two
formulations are combined within a single composition, for example
a dual-release composition.
[0102] K. Combination Active Agent Compositions
[0103] The invention encompasses the nanoparticulate nimesulide
compositions of the invention formulated or co-administered with
one or more non-nimesulide active agents. Methods of using such
combination compositions are also encompassed by the invention. The
non-nimesulide active agents can be present in a crystalline phase,
an amorphous phase, a semi-crystalline phase, a semi-amorphous
phase, or a mixture thereof.
[0104] The compound to be administered in combination with a
nanoparticulate nimesulide composition of the invention can be
formulated separately from the nanoparticulate nimesulide
composition or co-formulated with the nanoparticulate nimesulide
composition. Where a nanoparticulate nimesulide composition is
co-formulated with a second active agent, the second active agent
can be formulated in any suitable manner, such as
immediate-release, rapid-onset, sustained-release, or dual-release
form.
[0105] Such non-nimesulide active agents can be, for example, a
therapeutic agent. A therapeutic agent can be a pharmaceutical
agent, including a biologic, such as proteins, peptides, and
nucleotides, or a diagnostic agent, such as a contrast agent,
including x-ray contrast agents. The active agent can be selected
from a variety of known classes of drugs, including, for example,
amino acids, proteins, peptides, nucleotides, anti-obesity drugs,
central nervous system stimulants, carotenoids, corticosteroids,
elastase inhibitors, anti-fungals, oncology therapies,
anti-emetics, analgesics, cardiovascular agents, anti-inflammatory
agents, such as NSAIDs and COX-2 inhibitors, anthelmintics,
anti-arrhythmic agents, antibiotics (including penicillins),
anticoagulants, antidepressants, antidiabetic agents,
antiepileptics, antihistamines, antihypertensive agents,
antimuscarinic agents, antimycobacterial agents, antineoplastic
agents, immunosuppressants, antithyroid agents, antiviral agents,
anxiolytics, sedatives (hypnotics and neuroleptics), astringents,
alpha-adrenergic receptor blocking agents, beta-adrenoceptor
blocking agents, blood products and substitutes, cardiac inotropic
agents, contrast media, corticosteroids, cough suppressants
(expectorants and mucolytics), diagnostic agents, diagnostic
imaging agents, diuretics, dopaminergics (antiparkinsonian agents),
haemostatics, immunological agents, lipid regulating agents, muscle
relaxants, parasympathomimetics, parathyroid calcitonin and
biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones
(including steroids), anti-allergic agents, stimulants and
anoretics, sympathomimetics, thyroid agents, vasodilators,
vasomodulators, and xanthines.
[0106] Examples of representative active agents useful in this
invention include, but are not limited to, acyclovir, alprazolam,
altretamine, amiloride, amiodarone, benztropine mesylate,
bupropion, cabergoline, candesartan, cerivastatin, chlorpromazine,
ciprofloxacin, cisapride, clarithromycin, clonidine, clopidogrel,
cyclobenzaprine, cyproheptadine, delavirdine, desmopressin,
diltiazem, dipyridamole, dolasetron, enalapril maleate,
enalaprilat, famotidine, felodipine, furazolidone, glipizide,
irbesartan, ketoconazole, lansoprazole, loratadine, loxapine,
mebendazole, mercaptopurine, milrinone lactate, minocycline,
mitoxantrone, nelfinavir mesylate, nimodipine, norfloxacin,
olanzapine, omeprazole, penciclovir, pimozide, tacolimus, quazepam,
raloxifene, rifabutin, rifampin, risperidone, rizatriptan,
saquinavir, sertraline, sildenafil, acetyl-sulfisoxazole,
temazepam, thiabendazole, thioguanine, trandolapril, triamterene,
trimetrexate, troglitazone, trovafloxacin, verapamil, vinblastine
sulfate, mycophenolate, atovaquone, atovaquone, proguanil,
ceftazidime, cefuroxime, etoposide, terbinafine, thalidomide,
fluconazole, amsacrine, dacarbazine, teniposide, and
acetylsalicylate.
[0107] A description of these classes of active agents and a
listing of species within each class can be found in Martindale's
The Extra Pharmacopoeia, 31.sup.st Edition (The Pharmaceutical
Press, London, 1996), specifically incorporated by reference. The
active agents are commercially available and/or can be prepared by
techniques known in the art.
[0108] Exemplary nutraceuticals or dietary supplements include, but
are not limited to, lutein, folic acid, fatty acids (e.g., DHA and
ARA), fruit and vegetable extracts, vitamin and mineral
supplements, phosphatidylserine, lipoic acid, melatonin,
glucosamine/chondroitin, Aloe Vera, Guggul, glutamine, amino acids
(e.g., arginine, iso-leucine, leucine, lysine, methionine,
phenylanine, threonine, tryptophan, and valine), green tea,
lycopene, whole foods, food additives, herbs, phytonutrients,
antioxidants, flavonoid constituents of fruits, evening primrose
oil, flax seeds, fish and marine animal oils, and probiotics.
Nutraceuticals and dietary supplements also include bio-engineered
foods genetically engineered to have a desired property, also known
as "pharmafoods."
[0109] Exemplary nutraceuticals and dietary supplements are
disclosed, for example, in Roberts et al., Nutraceuticals: The
Complete Encyclopedia of Supplements, Herbs, Vitamins, and Healing
Foods (American Nutraceutical Association, 2001), which is
specifically incorporated by reference. Dietary supplements and
nutraceuticals are also disclosed in Physicians' Desk Reference for
Nutritional Supplements, 1st Ed. (2001) and The Physicians' Desk
Reference for Herbal Medicines, 1 st Ed. (2001), both of which are
also incorporated by reference. A nutraceutical or dietary
supplement, also known as a phytochemical or functional food, is
generally any one of a class of dietary supplements, vitamins,
minerals, herbs, or healing foods that have medical or
pharmaceutical effects on the body.
[0110] Preferred combination therapies comprise a composition
useful in methods of the invention with one or more compounds
selected from aceclofenac, acemetacin, e-acetamidocaproic acid,
acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid
(aspirin), S-adenosylmethionine, alclofenac, alfentanil,
allylprodine, alminoprofen, aloxiprin, alphaprodine, aluminum
bis(acetylsalicylate), amfenac, aminochlorthenoxazin,
3-amino-4-hydroxybutyric acid, 2-amino-4-picoline, aminopropylon,
aminopyrine, amixetrine, ammonium salicylate, ampiroxicam,
amtolmetin guacil, anileridine, antipyrine, antipyrine salicylate,
antrafenine, apazone, bendazac, benorylate, benoxaprofen,
benzpiperylon, benzydamine, benzylmorphine, bermoprofen,
bezitramide, .alpha.-bisabolol, bromfenac, p-bromoacetanilide,
5-bromosalicylic acid acetate, bromosaligenin, bucetin, bucloxic
acid, bucolome, bufexamac, bumadizon, buprenorphine, butacetin,
butibufen, butophanol, calcium acetylsalicylate, carbamazepine,
carbiphene, carprofen, carsalam, chlorobutanol, chlorthenoxazin,
choline salicylate, cinchophen, cinmetacin, ciramadol, clidanac,
clometacin, clonitazene, clonixin, clopirac, clove, codeine,
codeine methyl bromide, codeine phosphate, codeine sulfate,
cropropamide, crotethamide, desomorphine, dexoxadrol,
dextromoramide, dezocine, diampromide, diclofenac sodium,
difenamizole, difenpiramide, diflunisal, dihydrocodeine,
dihydrocodeinone enol acetate, dihydromorphine, dihydroxyaluminum
acetylsalicylate, dimenoxadol, dimepheptanol, dimethylthiambutene,
dioxaphetyl butyrate, dipipanone, diprocetyl, dipyrone, ditazol,
droxicam, emorfazone, enfenamic acid, epirizole, eptazocine,
etersalate, ethenzamide, ethoheptazine, ethoxazene,
ethylmethylthiambutene, ethylmorphine, etodolac, etofenamate,
etonitazene, eugenol, felbinac, fenbufen, fenclozic acid, fendosal,
fenoprofen, fentanyl, fentiazac, fepradinol, feprazone,
floctafenine, flufenamic acid, flunoxaprofen, fluoresone,
flupirtine, fluproquazone, flurbiprofen, fosfosal, gentisic acid,
glafenine, glucametacin, glycol salicylate, guaiazulene,
hydrocodone, hydromorphone, hydroxypethidine, ibufenac, ibuprofen,
ibuproxam, imidazole salicylate, indomethacin, indoprofen,
isofezolac, isoladol, isomethadone, isonixin, isoxepac, isoxicam,
ketobemidone, ketoprofen, ketorolac, p-lactophenetide, lefetamine,
levorphanol, lofentanil, lonazolac, lomoxicam, loxoprofen, lysine
acetylsalicylate, magnesium acetylsalicylate, meclofenamic acid,
mefenamic acid, meperidine, meptazinol, mesalamine, metazocine,
methadone hydrochloride, methotrimeprazine, metiazinic acid,
metofoline, metopon, mofebutazone, mofezolac, morazone, morphine,
morphine hydrochloride, morphine sulfate, morpholine salicylate,
myrophine, nabumetone, nalbuphine, 1-naphthyl salicylate, naproxen,
narceine, nefopam, nicomorphine, nifenazone, niflumic acid,
nimesulide, 5'-nitro-2'-propoxyacetanilide, norlevorphanol,
normethadone, normorphine, norpipanone, olsalazine, opium,
oxaceprol, oxametacine, oxaprozin, oxycodone, oxyrnorphone,
oxyphenbutazone, papaveretum, paranyline, parsalmide, pentazocine,
perisoxal, phenacetin, phenadoxone, phenazocine, phenazopyridine
hydrochloride, phenocoll, phenoperidine, phenopyrazone, phenyl
acetylsalicylate, phenylbutazone, phenyl salicylate, phenyramidol,
piketoprofen, piminodine, pipebuzone, piperylone, piprofen,
pirazolac, piritramide, piroxicam, pranoprofen, proglumetacin,
proheptazine, promedol, propacetamol, propiram, propoxyphene,
propyphenazone, proquazone, protizinic acid, ramifenazone,
remifentanil, rimazolium metilsulfate, salacetamide, salicin,
salicylamide, salicylamide o-acetic acid, salicylsulfuric acid,
salsalte, salverine, simetride, sodium salicylate, sufentanil,
sulfasalazine, sulindac, superoxide dismutase, suprofen,
suxibuzone, talniflumate, tenidap, tenoxicam, terofenamate,
tetrandrine, thiazolinobutazone, tiaprofenic acid, tiaramide,
tilidine, tinoridine, tolfenamic acid, tolmetin, tramadol,
tropesin, viminol, xenbucin, ximoprofen, zaltoprofen, and
zomepirac. See The Merck Index, 12th Edition (1996), Therapeutic
Category and Biological Activity Index, lists therein headed
"Analgesic", "Anti-inflammatory", and "Antipyretic").
[0111] In a particularly preferred embodiment of the invention, the
nanoparticulate nimesulide composition is combined with at least
one analgesic. Useful analgesics include, for example, NSAIDS and
non-nimesulide COX-2 inhibitors.
[0112] Particularly preferred combination therapies comprise use of
a nanoparticulate nimesulide composition of the invention with an
opioid compound, more particularly where the opioid compound is
codeine, meperidine, morphine, or a derivative thereof.
[0113] In an embodiment of the invention, particularly where a
COX-2 mediated condition is headache or migraine, the
nanoparticulate nimesulide composition is administered in
combination therapy with a vasomodulator, preferably a xanthine
derivative having vasomodulatory effect, more preferably an
alkylxanthine compound.
[0114] Combination therapies wherein an alkylxanthine compound is
co-administered with a nanoparticulate nimesulide composition as
provided herein are embraced by the present embodiment of the
invention whether or not the alkylxanthine is a vasomodulator and
whether or not the therapeutic effectiveness of the combination is
to any degree attributable to a vasomodulatory effect. The term
"alkylxanthine" herein embraces xanthine derivatives having one or
more C.sub.1-4 alkyl substituents, preferably methyl, and
pharmaceutically acceptable salts of such xanthine derivatives.
Dimethylxanthines and trimethylxanthines, including caffeine,
theobromine, and theophylline, are especially preferred. Most
preferably, the alkylxanthine compound is caffeine.
[0115] Exemplary NSAIDS that can be formulated in combination with
the nanoparticulate nimesulide composition of the invention
include, but are not limited to, suitable nonacidic and acidic
compounds. Suitable nonacidic compounds include, for example,
nabumetone, tiaramide, proquazone, bufexamac, flumizole, epirazole,
tinoridine, timegadine, and dapsone.
[0116] Exemplary acidic NSAID compounds that can be formulated in
combination with the nanoparticulate nimesulide composition of the
invention include, but are not limited to, carboxylic acids and
enolic acids. Suitable carboxylic acid NSADs include, for example:
(1) salicylic acids and esters thereof, such as aspirin,
diflunisal, benorylate, and fosfosal; (2) acetic acids, including
phenylacetic acids such as diclofenac, alclofenac and fenclofenac;
(3) carbo- and heterocyclic acetic acids such as etodolac,
indomethacin, sulindac, tolmetin, fentiazac, and tilomisole; (4)
propionic acids, such as carprofen, fenbufen, flurbiprofen,
ketoprofen, oxaprozin, suprofen, tiaprofenic acid, ibuprofen,
naproxen, fenoprofen, indoprofen, pirprofen; and (5) fenamic acids,
such as flufenamic, mefenamic, meclofenamic and niflumic. Suitable
enolic acid NSAIDs that can be formulated in combination with the
nanoparticulate nimesulide composition of the invention include,
but are not limited to: (1) pyrazolones such as oxyphenbutazone,
phenylbutazone, apazone, and feprazone; and (2) oxicams such as
piroxicam, sudoxicam, isoxicam, and tenoxicam.
[0117] Exemplary COX-2 inhibitors that can be formulated in
combination with the nanoparticulate nimesulide composition of the
invention include, but are not limited to, celecoxib (SC-58635,
CELEBREX.RTM., Pharmacia/Searle & Co.), rofecoxib (MK-966,
L-748731, VIOXX.RTM., Merck & Co.), meloxicam (MOBIC.RTM.,
co-marketed by Abbott Laboratories, Chicago, Ill., and Boehringer
Ingelheim Pharmaceuticals), valdecoxib (BEXTRA.RTM., G.D. Searle
& Co.), parecoxib (G.D. Searle & Co.), etoricoxib (MK-663;
Merck), SC-236 (chemical name of
4-[5-(4-chlorophenyl)-3-(trifluoromethyl- )-1H-pyrazol-1-yl)]
benzenesulfonamide; G.D. Searle & Co., Skokie, Ill.); NS-398
(N-(2-cyclohexyloxy-4-nitrophenyl)methane sulfonamide; Taisho
Pharmaceutical Co., Ltd., Japan); SC-58125 (methyl sulfone
spiro(2.4)hept-5-ene I; Pharmacia/Searle & Co.); SC-57666
(Pharmacia/Searle & Co.); SC-558 (Pharmacia/Searle & Co.);
SC-560 (Pharmacia/Searle & Co.); etodolac (Lodine.RTM.,
Wyeth-Ayerst Laboratories, Inc.); DFU
(5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulf- onyl)phenyl
2(5H)-furanone); monteleukast (MK-476), L-745337
((5-methanesulphonamide-6-(2,4-difluorothio-phenyl)-1-indanone),
L-761066, L-761000, L-748780 (all Merck & Co.); DUP-697
(5-Bromo-2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl; DuPont
Merck Pharmaceutical Co.); PGV 20229
(1-(7-tert.-butyl-2,3-dihydro-3,3-dimethyl-
benzo(b)furan-5-yl)-4-cyclopropylbutan-1-one; Procter & Gamble
Pharmaceuticals); iguratimod (T-614;
3-formylamino-7-methylsulfonylamino--
6-phenoxy-4H-1-benzopyran-4-one; Toyama Corp., Japan); BF 389
(Biofor, USA); CL 1004 (PD 136095), PD 136005, PD 142893, PD
138387, and PD 145065 (all Parke-Davis/Warner-Lambert Co.);
flurbiprofen (ANSAID.RTM.; Pharmacia & Upjohn); nabumetone
(FELAFEN.RTM.; SmithKline Beecham, plc); flosulide (CGP 28238;
Novartis/Ciba Geigy); piroxicam (FELDANE.RTM.; Pfizer); diclofenac
(VOLTAREN.RTM. and CATAFLAM.RTM., Novartis); lumiracoxib (COX-189;
Novartis); D 1367 (Celltech Chiroscience, plc); R 807 (3
benzoyldifluoromethane sulfonanilide, diflumidone); JTE-522 (Japan
Tobacco, Japan); FK-3311
(4'-Acetyl-2'-(2,4-difluorophenoxy)methanesulfon- anilide), FK 867,
FR 140423, and FR 115068 (all Fujisawa, Japan); GR 253035 (Glaxo
Wellcome); RWJ 63556 (Johnson & Johnson); RWJ 20485 (Johnson
& Johnson); ZK 38997 (Schering); S 2474
((E)-(5)-(3,5-di-tert-bu-
tyl-4-hydroxybenzylidene)-2-ethyl-1,2-isothiazolidine-1,1-dioxide
indomethacin; Shionogi & Co., Ltd., Japan); zomepirac analogs,
such as RS 57067 and RS 104897 (Hoffmann La Roche); RS 104894
(Hoffmann La Roche); SC 41930 (Monsanto); pranlukast (SB 205312,
Ono-1078, ONON.RTM., ULTAIRM; SmithKline Beecham); SB 209670
(SmithKline Beecham); and APHS (heptinylsulfide).
[0118] L. Miscellaneous Benefits of the Nanoparticulate Nimesulide
Compositions of the Invention
[0119] The nanoparticulate nimesulide compositions preferably
exhibit an increased rate of dissolution as compared to
microcrystalline or non-nanoparticulate forms of nimesulide. In
addition, the nanoparticulate nimesulide compositions preferably
exhibit improved performance characteristics for oral, intravenous,
subcutaneous, or intramuscular injection, such as higher dose
loading and smaller tablet or liquid dose volumes. Moreover, the
nanoparticulate nimesulide compositions of the invention do not
require organic solvents or pH extremes.
[0120] V. Compositions
[0121] The present invention includes nanoparticulate active agent
compositions that comprise nimesulide. The compositions preferably
comprise nimesulide and at least one surface stabilizer adsorbed
on, or associated with, the surface of the nimesulide. The
nanoparticulate nimesulide particles preferably have an effective
average particle size of less than about 2000 nm. In another
aspect, the invention provides novel combinations of nimesulide and
other active agents.
[0122] The invention also provides nanoparticulate nimesulide
compositions together with one or more non-toxic physiologically
acceptable carriers, adjuvants, or vehicles, collectively referred
to as carriers. The compositions can be formulated for various
routes of administration including, but not limited to, oral,
vaginal, rectal, nasal, ocular, parenteral injection (e.g.,
intravenous, intramuscular, or subcutaneous), local (e.g., in
powder, ointment or drop form), buccal, intracisternal,
intraperitoneal, or topical administration, and the like.
[0123] A. Nimesulide Particles
[0124] As used herein "nimesulide" means
N-(4-Nitro-2-phenoxy-phenyl)-meth- anesulfonamide, which has the
following structure: 2
[0125] or an analog or salt thereof. The nimesulide may be in a
crystalline phase, an amorphous phase, a semi-crystalline phase, a
semi-amorphous phase, or a mixture thereof.
[0126] Nanoparticulate nimesulide compositions are contemplated to
be useful for treating and/or preventing a wide range of conditions
and disorders mediated by COX-2, including but not limited to,
disorders characterized by inflammation, pain, and/or fever. Such
compositions are especially useful as anti-inflammatory agents,
such as in treatment of arthritis, with the additional benefit of
having significantly less harmful side effects than compositions of
conventional NSAIDs that lack selectivity for COX-2 over COX-1. In
particular, such compositions have reduced potential for
gastrointestinal toxicity and gastrointestinal irritation including
upper gastrointestinal ulceration and bleeding, reduced potential
for renal side effects such as reduction in renal function leading
to fluid retention and exacerbation of hypertension, reduced effect
on bleeding times including inhibition of platelet function, and
possibly a lessened ability to induce asthma attacks in
aspirin-sensitive asthmatic subjects, by comparison with
compositions of conventional NSAIDs.
[0127] Thus, nanoparticulate nimesulide compositions of the
invention are particularly useful as an alternative to conventional
NSAIDs where such NSAIDs are contraindicated, for example in
patients with peptic ulcers, gastritis, regional enteritis,
ulcerative colitis, diverticulitis, or with a recurrent history of
gastrointestinal lesions; gastrointestinal bleeding; coagulation
disorders including anemia such as hypoprothrombinemia, hemophilia,
or other bleeding problems; kidney disease; or in patients prior to
surgery or patients taking anticoagulants.
[0128] Because of the rapid onset of therapeutic effect observed
with the compositions of the invention, these compositions have
particular advantages over prior conventional formulations for
treatment of acute COX-2 mediated disorders, especially for relief
of pain, for example in headache, including sinus headache and
migraine.
[0129] Nimesulide is also useful in treating and/or preventing, for
example, arthritic disorders, gastrointestinal conditions,
inflammatory conditions, pulmonary inflammation, opthalmic
diseases, central nervous systems disorders, pain,
inflammation-related cardiovascular disorders, angiogenesis-related
disorders, benign and malignant tumors, adenomatous polyps,
disorders of the female reproductive system such as endometriosis,
osteoporosis, dysmenorrhea, premature labor, asthma,
eosinophil-related disorders, pyrexia, bone resorption,
nephrotoxicity, hypotension, arthrosis, joint stiffness, kidney
disease, liver disease including hepatitis, acute mastitis,
diarrhea, colonic adenomas, bronchitis, allergic neuritis,
cytomegalovirus infectivity, apoptosis including HIV-induced
apoptosis, lumbago; skin-related conditions such as psoriasis,
eczema, acne, burns, dermatitis, and ultraviolet radiation damage
including sunburn; allergic rhinitis, respiratory distress
syndrome, and endotoxin shock syndrome. Nanoparticulate nimesulide
is also useful as an immunosuppressive agent.
[0130] Exemplary forms of arthritic disorders that can be treated
include, but are not limited to, osteoarthritis, rheumatoid
arthritis, spondyloarthropathies, gouty arthritis, juvenile
arthritis, gout, ankylosing spondylitis, systemic lupus
erythematosus, bursitis, tendinitis, myofascial pain, carpal tunnel
syndrome, fibromyalgia syndrome, infectious arthritis, psoriatic
arthritis, Reiter's syndrome, and scleroderma
[0131] Exemplary gastrointestinal conditions or ulcerative diseases
that can be treated include, but are not limited to, inflammatory
bowel disease, Crohn's disease, gastritis, irritable bowel
syndrome, ulcerative colitis, gastric ulcer, pathological but
non-malignant conditions such as hemangiomas, including infantile
hemaginomas, angiofibroma of the nasopharynx, and avascular
necrosis of bone.
[0132] Exemplary inflammation conditions that can be treated
include, but are not limited to, migraine headaches, periarteritis
nodosa, thyroiditis, aplastic anemia, Hodgkin's disease,
sclerodoma, rheumatic fever, type I diabetes, neuromuscular
junction disease including myasthenia gravis, white matter disease
including multiple sclerosis, sarcoidosis, nephrotic syndrome,
Behcet's syndrome, polymyositis, gingivitis, nephritis,
hypersensitivity, swelling occurring after injury including brain
edema, myocardial ischemia, post-operative inflammation including
that following ophthalmic surgery such as cataract surgery or
refractive surgery, and the like.
[0133] Exemplary pulmonary inflammation conditions that can be
treated include, but are not limited to, inflammation associated
with viral infections and cystic fibrosis, and in bone resorption
such as that associated with osteoporosis.
[0134] Exemplary opthalmic diseases or conditions that can be
treated include, but are not limited to, retinitis, conjunctivitis,
retinopathies, uveitis, ocular photophobia, acute injury to the eye
tissue, corneal graft rejection, ocular neovascularization, retinal
neovascularization including neovascularization following injury or
infection, diabetic retinopathy, macular degeneration, retrolental
fibroplasia, glaucoma, and neovascular glaucoma.
[0135] Exemplary central nervous system disorders that can be
treated include, but are not limited to, cortical dementias
including Alzheimer's disease, neurodegeneration, and central
nervous system damage resulting from stroke, ischemia, and trauma.
The term "treatment" in the present context includes partial or
total inhibition of dementias, including Alzheimer's disease,
vascular dementia, multi-infarct dementia, pre-senile dementia,
alcoholic dementia, and senile dementia.
[0136] Exemplary pain conditions that can be treated include, but
are not limited to, postoperative pain, pain resulting from battle
field wounds, dental pain, muscular pain, pain resulting from
cancer, headaches, including sinus headache and migraine, menstrual
cramps, and pain associated with inflammation.
[0137] Exemplary inflammation-related cardiovascular disorders that
can be treated or prevented using compositions of the invention
include, but are not limited to, vascular diseases, coronary artery
disease, aneurysm, vascular rejection, arteriosclerosis,
atherosclerosis including cardiac transplant atherosclerosis,
myocardial infarction, embolism, stroke, thrombosis including
venous thrombosis, angina including unstable angina, coronary
plaque inflammation, bacterial-induced inflammation including
Chlamydia-induced inflammation, viral induced inflammation, and
inflammation associated with surgical procedures such as vascular
grafting including coronary artery bypass surgery,
revascularization procedures including angioplasty, stent
placement, endarterectomy, or other invasive procedures involving
arteries, veins, and capillaries.
[0138] Exemplary angiogenesis-related disorders for which the
inventive compositions are useful include, but are not limited to,
inhibition of tumor angiogenesis. Such compositions also are useful
for treating neoplasia, including metastasis, benign and malignant
tumors, and neoplasia including cancer, such as colorectal cancer,
brain cancer, bone cancer, epithelial cell-derived neoplasia
(epithelial carcinoma) such as basal cell carcinoma,
adenocarcinoma, gastrointestinal cancer such as lip cancer, mouth
cancer, esophageal cancer, small bowel cancer, stomach cancer,
colon cancer, liver cancer, bladder cancer, pancreas cancer, ovary
cancer, cervical cancer, lung cancer, breast cancer, skin cancer
such as squamous cell and basal cell cancers, prostate cancer,
renal cell carcinoma, and other known cancers that effect
epithelial cells throughout the body. Neoplasias for which
compositions of the invention are contemplated to be particularly
useful are gastrointestinal cancer, Barrett's esophagus, liver
cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate
cancer, cervical cancer, lung cancer, breast cancer and skin
cancer. The nanoparticulate nimesulide compositions of the
invention can also be used to treat fibrosis that occurs with
radiation therapy.
[0139] The compositions of the invention can be used to treat
subjects having adenomatous polyps, including those with familial
adenomatous polyposis (FAP). Additionally, such compositions can be
used to prevent polyps from forming in patients at risk of FAP.
[0140] Because the nimesulide compositions of the invention inhibit
prostanoid-induced smooth muscle contraction by inhibiting
synthesis of contractile prostanoids, the compositions can be used
in the treatment of dysmenorrhea, premature labor, asthma, and
eosinophil-related disorders.
[0141] The compositions of the invention are also useful in
treating indications where anti-inflammatory agents,
anti-angiogenesis agents, antitumorigenic agents, immunosuppressive
agents, NSAIDs, COX-2 inhibitors, analgesic agents, anti-thrombotic
agents, narcotics, or antifebrile agents are typically used.
[0142] B. Surface Stabilizers
[0143] Surface stabilizers especially useful herein physically
adhere on or associate with the surface of nanoparticulate
nimesulide particles, but do not chemically react with the
nimesulide particles or themselves. Preferably, individual
molecules of the surface stabilizer are essentially free of
intermolecular cross-linkages.
[0144] Combinations of more than one surface stabilizer can be used
in the invention. Useful surface stabilizers include, but are not
limited to, known organic and inorganic pharmaceutical excipients.
Such excipients include various polymers, low molecular weight
oligomers, natural products, and surfactants. Preferred surface
stabilizers include nonionic, ionic, anionic, cationic, and
zwitterionic surfactants.
[0145] Representative examples of surface stabilizers include
hydroxypropylmethylcellulose, hydroxypropylcellulose,
polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate,
gelatin, casein, lecithin (phosphatides), dextran, gum acacia,
cholesterol, tragacanth, stearic acid, benzalkonium chloride,
calcium stearate, glycerol monostearate, cetostearyl alcohol,
cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene
alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000),
polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan
fatty acid esters (e.g., the commercially available Tweens.RTM.
such as e.g., Tween 20.RTM. and Tween 80.RTM. (ICI Speciality
Chemicals)); polyethylene glycols (e.g., Carbowaxs 3550.RTM. and
934.RTM. (Union Carbide)), polyoxyethylene stearates, colloidal
silicon dioxide, phosphates, carboxymethylcellulose calcium,
carboxymethylcellulose sodium, methyl cellulose,
hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate,
noncrystalline cellulose, magnesium aluminium silicate,
triethanolamine, polyvinyl alcohol (PVA),
4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and
formaldehyde (also known as tyloxapol, superione, and triton),
poloxamers (e.g., Pluronics F68.RTM. and F108.RTM., which are block
copolymers of ethylene oxide and propylene oxide); poloxamines
(e.g., Tetronic 908.RTM., also known as Poloxamine 908.RTM., which
is a tetrafunctional block copolymer derived from sequential
addition of propylene oxide and ethylene oxide to ethylenediamine
(BASF Wyandotte Corporation, Parsippany, N.J.)); Tetronic 1508.RTM.
(T-1508) (BASF Wyandotte Corporation), Triton X-200.RTM., which is
an alkyl aryl polyether sulfonate (Dow Chemical); Crodestas
F-10.RTM., which is a mixture of sucrose stearate and sucrose
distearate (Croda Inc.); p-isononylphenoxypoly-(glycidol), also
known as Olin-lOG.RTM. or Surfactant 10-G.RTM. (Olin Chemicals,
Stamford, Conn.); Crodestas SL-40.RTM. (Croda, Inc.); and SA9OHCO,
which is C.sub.18H.sub.37CH.sub.2C-
(O)N(CH.sub.3)--CH.sub.2(CHOH).sub.4(CH.sub.2OH).sub.2 (Eastman
Kodak Co.); decanoyl-N-methylglucamide; n-decyl
.beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside;
n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside;
heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside;
n-heptyl .beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside;
nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside;
octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl
.beta.-D-thioglucopyranoside; PEG-derivatized phospholipid,
PEG-derivatized cholesterol, PEG-derivatized cholesterol
derivative, PEG-derivatized vitamin A, PEG-derivatized vitamin E,
lysozyme, random copolymers of vinyl pyrrolidone and vinyl acetate,
and the like such as Plasdone.RTM. S630 in a 60:40 ratio of the
pyrrolidone and vinyl acetate.
[0146] More examples of useful surface stabilizers include, but are
not limited to, polymers, biopolymers, polysaccharides,
cellulosics, alginates, phospholipids, and nonpolymeric compounds,
such as zwitterionic stabilizers, poly-n-methylpyridinium, anthryul
pyridinium chloride, cationic phospholipids, chitosan, polylysine,
polyvinylimidazole, polybrene, polymethylmethacrylate
trimethylammoniumbromide bromide (PMMTMABr),
hexadecyltrimethylammonium bromide (HDMAB), and
polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl
sulfate.
[0147] Other useful cationic stabilizers include, but are not
limited to, cationic lipids, sulfonium, phosphonium, and quartemary
ammonium compounds, such as stearyltrimethylammonium chloride,
benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl
ammonium chloride or bromide, coconut methyl dihydroxyethyl
ammonium chloride or bromide, decyl triethyl ammonium chloride,
decyl dimethyl hydroxyethyl ammonium chloride or bromide,
C.sub.12-15dimethyl hydroxyethyl ammonium chloride or bromide,
coconut dimethyl hydroxyethyl ammonium chloride or bromide,
myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl
ammonium chloride or bromide, lauryl dimethyl (ethenoxy).sub.4
ammonium chloride or bromide, N-alkyl (C.sub.12-18)dimethylbenzyl
ammonium chloride, N-alkyl (C.sub.14-18)dimethyl-benzyl ammonium
chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate,
dimethyl didecyl ammonium chloride, N-alkyl and (C.sub.12-14)
dimethyl 1-napthylmethyl ammonium chloride, trimethylammonium
halide, alkyl-trimethylammonium salts and dialkyl-dimethylammonium
salts, lauryl trimethyl ammonium chloride, ethoxylated
alkyamidoalkyldialkylammonium salt and/or an ethoxylated trialkyl
ammonium salt, dialkylbenzene dialkylammonium chloride,
N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl
ammonium, chloride monohydrate, N-alkyl(C.sub.12-14) dimethyl
1-naphthylmethyl ammonium chloride and dodecyldimethylbenzyl
ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl
trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride,
alkyl benzyl dimethyl ammonium bromide, C.sub.12, C.sub.15,
C.sub.17 trimethyl ammonium bromides, dodecylbenzyl triethyl
ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC),
dimethyl ammonium chlorides, alkyldimethylammonium halogenides,
tricetyl methyl ammonium chloride, decyltrimethylammonium bromide,
dodecyltriethylammonium bromide, tetradecyltrimethylammonium
bromide, methyl trioctylammonium chloride (ALIQUAT 336.TM.),
POLYQUAT 10.TM., tetrabutylammonium bromide, benzyl
trimethylammonium bromide, choline esters (such as choline esters
of fatty acids), benzalkonium chloride, stearalkonium chloride
compounds (such as stearyltrimonium chloride and Di-stearyldimonium
chloride), cetyl pyridinium bromide or chloride, halide salts of
quaternized polyoxyethylalkylamines, MIRAPOL.TM. and ALKAQUAT.TM.
(Alkaril Chemical ComPany), alkyl pyridinium salts; amines, such as
alkylamines, dialkylamines, alkanolamines, polyethylenepolyamines,
N,N-dialkylaminoalkyl acrylates, and vinyl pyridine, amine salts,
such as lauryl amine acetate, stearyl amine acetate,
alkylpyridinium salt, and alkylimidazolium salt, and amine oxides;
imide azolinium salts; protonated quaternary acrylamides;
methylated quaternary polymers, such as poly[diallyl
dimethylammonium chloride] and poly-[N-methyl vinyl pyridinium
chloride]; and cationic guar.
[0148] Such exemplary cationic surface stabilizers and other useful
cationic surface stabilizers are described in J. Cross and E.
Singer, Cationic Surfactants: Analytical and Biological Evaluation
(Marcel Dekker, 1994); P. and D. Rubingh (Editor), Cationic
Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J.
Richmond, Cationic Surfactants: Organic Chemistry, (Marcel Dekker,
1990).
[0149] Nonpolymeric surface stabilizers include nonpolymeric
compounds, such benzalkonium chloride, a carbonium compound, a
phosphonium compound, an oxonium compound, a halonium compound, a
cationic organometallic compound, a quartemary phosphorous
compound, a pyridinium compound, an anilinium compound, an ammonium
compound, a hydroxylammonium compound, a primary ammonium compound,
a secondary ammonium compound, a tertiary ammonium compound, and
quarternary ammonium compounds of the formula
NR.sub.1R.sub.2R.sub.3R.sub.4.sup.(+). For compounds of the formula
NR.sub.1R.sub.2R.sub.3R.sub.4.sup.(+):
[0150] (i) none of R.sub.1-R.sub.4 are CH.sub.3;
[0151] (ii) one of R.sub.1-R.sub.4 is CH.sub.3;
[0152] (iii) three of R.sub.1-R.sub.4 are CH.sub.3;
[0153] (iv) all of R.sub.1-R.sub.4 are CH.sub.3;
[0154] (v) two of R.sub.1-R.sub.4 are CH.sub.3, one of
R.sub.1-R.sub.4 is C.sub.6H.sub.5CH.sub.2, and one of
R.sub.1-R.sub.4 is an alkyl chain of seven carbon atoms or
less;
[0155] (vi) two of R.sub.1-R.sub.4 are CH.sub.3, one of
R.sub.1-R.sub.4 is C.sub.6H.sub.5CH.sub.2, and one of
R.sub.1-R.sub.4 is an alkyl chain of nineteen carbon atoms or
more;
[0156] (vii) two of R.sub.1-R.sub.4 are CH.sub.3 and one of
R.sub.1-R.sub.4 is the group C.sub.6H.sub.5(CH.sub.2).sub.n, where
n>1;
[0157] (viii) two of R.sub.1-R.sub.4 are CH.sub.3, one of
R.sub.1-R.sub.4 is C.sub.6H.sub.5CH.sub.2, and one of
R.sub.1-R.sub.4 comprises at least one heteroatom;
[0158] (ix) two of R.sub.1-R.sub.4 are CH.sub.3, one of
R.sub.1-R.sub.4 is C.sub.6H.sub.5CH.sub.2, and one of
R.sub.1-R.sub.4 comprises at least one halogen;
[0159] (x) two of R.sub.1-R.sub.4 are CH.sub.3, one of
R.sub.1-R.sub.4 is C.sub.6H.sub.5CH.sub.2, and one of
R.sub.1-R.sub.4 comprises at least one cyclic fragment;
[0160] (xi) two of R.sub.1-R.sub.4 are CH.sub.3 and one of
R.sub.1-R.sub.4 is a phenyl ring; or
[0161] (xii) two of R.sub.1-R.sub.4 are CH.sub.3 and two of
R.sub.1-R.sub.4 are purely aliphatic fragments.
[0162] Such compounds include, but are not limited to,
behenalkonium chloride, benzethonium chloride, cetylpyridinium
chloride, behentrimonium chloride, lauralkonium chloride,
cetalkonium chloride, cetrimonium bromide, cetrimonium chloride,
cethylamine hydrofluoride, chlorallylmethenamine chloride
(Quatemium-15), distearyldimonium chloride (Quaternium-5), dodecyl
dimethyl ethylbenzyl ammonium chloride (Quaternium-14),
Quaternium-22, Quatemium-26, Quaternium-18 hectorite,
dimethylaminoethylchloride hydrochloride, cysteine hydrochloride,
diethanolammonium POE (10) oletyl ether phosphate,
diethanolammonium POE (3)oleyl ether phosphate, tallow alkonium
chloride, dimethyl dioctadecylammoniumbentonite, stearalkonium
chloride, domiphen bromide, denatonium benzoate, myristalkonium
chloride, laurtrimonium chloride, ethylenediamine dihydrochloride,
guanidine hydrochloride, pyridoxine HCl, iofetamine hydrochloride,
meglumine hydrochloride, methylbenzethonium chloride, myrtrimonium
bromide, oleyltrimonium chloride, polyquaternium-1, proc
ainehydrochloride, cocobetaine, stearalkonium bentonite,
stearalkoniumhectonite, stearyl trihydroxyethyl propylenediamine
dihydrofluoride, tallowtrimonium chloride, and hexadecyltrimethyl
ammonium bromide.
[0163] Most of these surface stabilizers are known pharmaceutical
excipients and are described in detail in the Handbook of
Pharmaceutical Excipients, published jointly by the American
Pharmaceutical Association and The Pharmaceutical Society of Great
Britain (The Pharmaceutical Press, 2000), which is specifically
incorporated herein by reference.
[0164] Particularly preferred surface stabilizers include, but are
not limited to, a copovidone, such as Plasdone.RTM. S-630 (ISP) and
Kollidon.RTM. VA 64 (BASF), which are random copolymers of vinyl
pyrrolidone and vinyl acetate in a 60:40 ratio, hydroxypropylmethyl
cellulose, or tyloxapol.
[0165] Each of these surface stabilizers is commercially available
and/or can be prepared by techniques known in the art.
[0166] C. Other Pharmaceutical Excipients
[0167] Pharmaceutical compositions of the invention may also
comprise one or more binding agents, filling agents, lubricating
agents, suspending agents, sweeteners, flavoring agents,
preservatives, buffers, wetting agents, disintegrants, effervescent
agents, and other excipients depending upon the route of
administration and the dosage form desired. Such excipients are
well known in the art.
[0168] Examples of filling agents are lactose monohydrate, lactose
anhydrous, and various starches; examples of binding agents are
various celluloses and cross-linked polyvinylpyrrolidone,
microcrystalline cellulose, such as Avicel.RTM. PH101 and
Avicel.RTM. PH102, microcrystalline cellulose, and silicified
microcrystalline cellulose (ProSolv SMCC.TM.).
[0169] Suitable lubricants, including agents that act on the
flowability of the powder to be compressed, are colloidal silicon
dioxide, such as Aerosil.RTM. 200, talc, stearic acid, magnesium
stearate, calcium stearate, and silica gel.
[0170] Examples of sweeteners are any natural or artificial
sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate,
aspartame, and acsulfame. Examples of flavoring agents are
Magnasweet.RTM. (trademark of MAFCO), bubble gum flavor, and fruit
flavors, and the like.
[0171] Examples of preservatives are potassium sorbate,
methylparaben, propylparaben, benzoic acid and its salts, other
esters of parahydroxybenzoic acid such as butylparaben, alcohols
such as ethyl or benzyl alcohol, phenolic compounds such as phenol,
and quarternary compounds such as benzalkonium chloride.
[0172] Suitable diluents include pharmaceutically acceptable inert
fillers, such as microcrystalline cellulose, lactose, dibasic
calcium phosphate, saccharides, and/or mixtures of any of the
foregoing. Examples of diluents include microcrystalline cellulose,
such as Avicel.RTM. PH101 and Avicel.RTM. PH102; lactose such as
lactose monohydrate, lactose anhydrous, and Pharmatose.RTM. DCL21;
dibasic calcium phosphate such as Emcompress.RTM.; mannitol;
starch; sorbitol; sucrose; and glucose.
[0173] Suitable disintegrants include lightly crosslinked polyvinyl
pyrrolidone, corn starch, potato starch, maize starch, and modified
starches, croscarmellose sodium, cross-povidone, sodium starch
glycolate, and mixtures thereof.
[0174] Examples of effervescent agents are effervescent couples,
such as an organic acid and a carbonate or bicarbonate. Suitable
organic acids include, for example, citric, tartaric, malic,
fumaric, adipic, succinic, and alginic acids and anhydrides and
acid salts. Suitable carbonates and bicarbonates include, for
example, sodium carbonate, sodium bicarbonate, potassium carbonate,
potassium bicarbonate, magnesium carbonate, sodium glycine
carbonate, L-lysine carbonate, and arginine carbonate.
Alternatively, only the sodium bicarbonate component of the
effervescent couple may be present.
[0175] D. Nanoparticulate Nimesulide Particle Size
[0176] Compositions of the invention contain nimesulide
nanoparticles that have an effective average particle size of less
than about 2000 nm (i.e., 2 microns). In preferred embodiments of
the invention, the nimesulide nanoparticles have an effective
average particle size of less than about 1900 nm, less than about
1800 nm, less than about 1700 nm, less than about 1600 nm, less
than about 1500 nm, less than about 1400 nm, less than about 1300
nm, less than about 1200 nm, less than about 1100 nm, less than
about 1000 nm, less than about 900 nm, less than about 800 .mu.m,
less than about 700 nm, less than about 600 nm, less than about 500
nm, less than about 400 nm, less than about 300 nm, less than about
250 nm, less than about 200 nm, less than about 150 nm, less than
about 100 nm, less than about 75 nm, or less than about 50 nm, as
measured by light-scattering methods, microscopy, or other
appropriate methods.
[0177] An "effective average particle size of less than about 2000
nm" means that at least 50% of the nimesulide particles have a
particle size less than the effective average, by weight, i.e.,
less than about 2000 nm, about 1900 nm, about 1800 nm, etc., when
measured by the above-noted techniques. Preferably, at least about
70%, at least about 90%, at least about 95%, or at least about 99%
of the nimesulide particles have a particle size less than the
effective average, i.e., less than about 2000 nm, about 1900 nm,
about 1800 rn, etc.
[0178] In the present invention, the value for D50 of a
nanoparticulate nimesulide composition is the particle size below
which 50% of the nimesulide particles fall, by weight. Similarly,
D90 is the particle size below which 90% of the nimesulide
particles fall, by weight.
[0179] If the compositions of the invention also comprise
microparticulate nimesulide or non-nimesulide active agents, then
the particles of such compounds have an effective average particle
size greater than about 2 microns, which means that at least 50% of
the particles have a size greater than about 2 microns. In other
embodiments of the invention, at least about 70%, at least about
90%, at least about 95%, or at least about 99% of the nimesulide
microparticulate or non-nimesulide microparticulate particles have
a particle size greater than about 2 microns.
[0180] E. Concentration of Nanoparticulate Nimesulide and Surface
Stabilizers
[0181] The relative amounts of at least one nimesulide and one or
more surface stabilizers can vary widely. The optimal amount of the
individual components depends, for example, upon physical and
chemical attributes of the surface stabilizer(s) selected, such as
the hydrophilic lipophilic balance (HLB), melting point, and the
surface tension of water solutions of the stabilizer, etc.
[0182] Preferably, the concentration of nimesulide can vary from
about 99.5% to about 0.001%, from about 95% to about 0.1%, or from
about 90% to about 0.5%, by weight, based on the total combined
weight of the nimesulide and at least one surface stabilizer, not
including other excipients. Higher concentrations of the active
ingredient are generally preferred from a dose and cost efficiency
standpoint.
[0183] Preferably, the concentration of surface stabilizer can vary
from about 0.5% to about 99.999%, from about 5.0% to about 99.9%,
or from about 10% to about 99.5%, by weight, based on the total
combined dry weight of nimesulide and at least one surface
stabilizer, not including other excipients.
[0184] VI. Methods of Making Nanoparticulate Nimesulide
Compositions
[0185] Nanoparticulate nimesulide compositions can be made using
any suitable method known in the art such as, for example, milling,
homogenization, or precipitation techniques. Exemplary methods of
making nanoparticulate compositions are described in the '684
patent. Methods of making nanoparticulate compositions are also
described in U.S. Pat. No. 5,518,187 for "Method of Grinding
Pharmaceutical Substances;" U.S. Pat. No. 5,718,388 for "Continuous
Method of Grinding Pharmaceutical Substances;" U.S. Pat. No.
5,862,999 for "Method of Grinding Pharmaceutical Substances;" U.S.
Pat. No. 5,665,331 for "Co-Microprecipitation of Nanoparticulate
Pharmaceutical Agents with Crystal Growth Modifiers;" U.S. Pat. No.
5,662,883 for "Co-Microprecipitation of Nanoparticulate
Pharmaceutical Agents with Crystal Growth Modifiers;" U.S. Pat. No.
5,560,932 for "Microprecipitation of Nanoparticulate Pharmaceutical
Agents;" U.S. Pat. No. 5,543,133 for "Process of Preparing X-Ray
Contrast Compositions Containing Nanoparticles;" U.S. Pat. No.
5,534,270 for "Method of Preparing Stable Drug Nanoparticles;" U.S.
Pat. No. 5,510,118 for "Process of Preparing Therapeutic
Compositions Containing Nanoparticles;" and U.S. Pat. No. 5,470,583
for "Method of Preparing Nanoparticle Compositions Containing
Charged Phospholipids to Reduce Aggregation," all of which are
specifically incorporated herein by reference.
[0186] The resultant nanoparticulate nimesulide compositions or
dispersions can be utilized in solid, semi-solid, or liquid dosage
formulations, such as liquid dispersions, gels, aerosols,
ointments, creams, controlled release formulations, fast melt
formulations, lyophilized formulations, tablets, capsules, delayed
release formulations, extended release formulations, pulsatile
release formulations, mixed immediate release and controlled
release formulations, etc. Solid dose forms of the dispersions of
novel nimesulide formulations according to the present invention
can be made as described in U.S. Pat. No. 6,375,986.
[0187] A. Milling to Obtain Nanoparticulate Nimesulide
Dispersions
[0188] Milling nimesulide to obtain a nanoparticulate nimesulide
dispersion comprises dispersing nimesulide particles in a liquid
dispersion media in which the nimesulide is poorly soluble,
followed by applying mechanical means in the presence of grinding
media to reduce the particle size of the nimesulide to the desired
effective average particle size. The dispersion media can be, for
example, water, safflower oil, ethanol, t-butanol, glycerin,
polyethylene glycol (PEG), hexane, or glycol. Water is a preferred
dispersion media.
[0189] The nimesulide particles can be reduced in size preferably
in the presence of at least one surface stabilizer. Alternatively,
the nimesulide particles can be contacted with one or more surface
stabilizers after attrition. Other compounds, such as a diluent,
can be added to the nimesulide/surface stabilizer composition
during the particle size reduction process. Dispersions can be
manufactured continuously or in a batch mode.
[0190] B. Precipitation to Obtain Nanoparticulate Nimesulide
Compositions
[0191] Another method of forming a nanoparticulate nimesulide
composition is microprecipitation. This involves preparing stable
dispersions of poorly soluble active agents in the presence of one
or more surface stabilizers and one or more colloid stability
enhancing surface active agents free of any trace toxic solvents or
solubilized heavy metal impurities. Such a method comprises, for
example: (1) dissolving nimesulide in a suitable solvent; (2)
adding the formulation from step (1) to a solution comprising at
least one surface stabilizer; and (3) precipitating the formulation
from step (2) using an appropriate non-solvent. The method can be
followed by removal of any formed salt, if present, by dialysis or
diafiltration and concentration of the dispersion by conventional
means.
[0192] C. Homogenization to Obtain Nimesulide Nanoparticulate
Compositions
[0193] Exemplary homogenization methods of preparing active agent
nanoparticulate compositions are described in U.S. Pat. No.
5,510,118, for "Process of Preparing Therapeutic Compositions
Containing Nanoparticles." Such a method comprises dispersing
nimesulide particles in a liquid dispersion media in which the
nimesulide is poorly soluble, followed by subjecting the dispersion
to homogenization to reduce the particle size of the nimesulide to
the desired effective average particle size. The nimesulide
particles can be reduced in size in the presence of at least one
surface stabilizer. Alternatively, the nimesulide particles can be
contacted with one or more surface stabilizers either before or
after attrition. Other compounds, such as a diluent, can be added
to the nimesulide/surface stabilizer composition either before,
during, or after the size reduction process. Dispersions can be
manufactured continuously or in a batch mode.
[0194] VII. Methods of Using Nimesulide Formulations of the
Invention
[0195] Nimesulide compositions of the invention can be administered
to a subject via any conventional means including, but not limited
to, preferably orally, vaginally, rectally, ocularly, parenterally
(e.g., intravenous, intramuscular, or subcutaneous),
intracisternally, pulmonary, intravaginally, intraperitoneally,
topically, locally (e.g., powders, ointments or drops), or as a
buccal or nasal spray. As used herein, the term "subject" is used
to mean an animal, preferably a mammal, including a human or
non-human. The terms patient and subject may be used
interchangeably.
[0196] The present invention provides a method of prolonging plasma
levels of nimesulide in a subject while achieving the desired
therapeutic effect.
[0197] In one aspect, compositions of the invention are
administered for treating conditions characterized by pain,
inflammation, or fever. Many such conditions are set forth
above.
[0198] Compositions suitable for parenteral injection may comprise
physiologically acceptable sterile aqueous or nonaqueous solutions,
dispersions, suspensions or emulsions, and sterile powders for
reconstitution into sterile injectable solutions or dispersions.
Examples of suitable aqueous and nonaqueous carriers, diluents,
solvents, or vehicles include water, ethanol, polyols
(propyleneglycol, polyethyleneglycol, glycerol, and the like),
suitable mixtures thereof, vegetable oils (such as olive oil) and
injectable organic esters such as ethyl oleate. Proper fluidity can
be maintained, for example, by the use of a coating such as
lecithin, by the maintenance of the required particle size in the
case of dispersions, and by the use of surfactants.
[0199] The nanoparticulate nimesulide compositions may also contain
adjuvants such as preserving, wetting, emulsifying, and dispensing
agents. Prevention of the growth of microorganisms can also be
ensured by various antibacterial and antifungal agents, such as
parabens, chlorobutanol, phenol, sorbic acid, and the like. It may
also be desirable to include isotonic agents, such as sugars,
sodium chloride, and the like. Prolonged absorption of the
injectable pharmaceutical form can be brought about by the use of
agents delaying absorption, such as aluminum monostearate and
gelatin.
[0200] Solid dosage forms for oral administration are preferred and
include, but are not limited to, capsules, tablets, pills, powders,
caplets, and granules. In such solid dosage forms, the active agent
(i.e. the composition of this invention) is admixed with at least
one of the following: (a) one or more inert excipients (or
carriers), such as sodium citrate or dicalcium phosphate; (b)
fillers or extenders, such as starches, lactose, sucrose, glucose,
mannitol, and silicic acid; (c) binders, such as
carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,
sucrose, and acacia; (d) humectants, such as glycerol; (e)
disintegrating agents, such as agar-agar, calcium carbonate, potato
or tapioca starch, alginic acid, certain complex silicates, and
sodium carbonate; (f) solution retarders, such as paraffin; (g)
absorption accelerators, such as quaternary ammonium compounds; (h)
wetting agents, such as cetyl alcohol and glycerol monostearate;
(i) adsorbents, such as kaolin and bentonite; and (j) lubricants,
such as talc, calcium stearate, magnesium stearate, solid
polyethylene glycols, sodium lauryl sulfate, or mixtures thereof.
For capsules, tablets, and pills, the dosage forms may also
comprise buffering agents.
[0201] Liquid dosage forms for oral administration include
pharmaceutically acceptable dispersions, emulsions, solutions,
suspensions, syrups, and elixirs. In addition to the active agent,
the liquid dosage forms may comprise inert diluents commonly used
in the art, such as water or other solvents, solubilizing agents,
and emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl
alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl
benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide,
oils, such as cottonseed oil, groundnut oil, corn germ oil, olive
oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl
alcohol, polyethyleneglycols, fatty acid esters of sorbitan, or
mixtures of these substances, and the like.
[0202] Besides such inert diluents, the composition can also
include adjuvants, such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0203] Effective amounts of the inventive nimesulide compositions
can be determined empirically. The compositions can be employed in
pure form or, where such forms exist, in pharmaceutically
acceptable salt, ester, or prodrug form. Actual dosage levels of
nimesulide in the inventive nanoparticulate compositions may be
varied to obtain an amount of nimesulide that is effective to
obtain a desired therapeutic response for a particular composition,
method of administration and condition to be treated. The selected
dosage level therefore depends upon the desired therapeutic effect,
the route of administration, the potency of the administered
nimesulide, the desired duration of treatment, and other
factors.
[0204] Dosage unit compositions may contain such amounts of such
submultiples thereof as may be used to make up the daily dose. It
will be understood, however, that the specific dose level for any
particular patient will depend upon a variety of factors: the type
and degree of the cellular or physiological response to be
achieved; activity of the specific agent or composition employed;
the specific agents or composition employed; the age, body weight,
general health, sex, and diet of the patient; the time of
administration, route of administration, and rate of excretion of
the agent; the duration of the treatment; drugs used in combination
or coincidental with the specific agent; and like factors well
known in the medical arts.
[0205] A. Treatment Applications
[0206] Nanoparticulate nimesulide compositions are useful for
treating and/or preventing a wide range of conditions and disorders
mediated by COX-2, including but not limited to, disorders
characterized by inflammation, pain, and/or fever. Such
compositions are especially useful as anti-inflammatory agents,
such as in treatment of arthritis, with the additional benefit of
having significantly less harmful side effects than compositions of
conventional NSAIDs that lack selectivity for COX-2 over COX-1. In
particular, such compositions have reduced potential for
gastrointestinal toxicity and gastrointestinal irritation including
upper gastrointestinal ulceration and bleeding, reduced potential
for renal side effects such as reduction in renal function leading
to fluid retention and exacerbation of hypertension, reduced effect
on bleeding times including inhibition of platelet function, and
possibly a lessened ability to induce asthma attacks in
aspirin-sensitive asthmatic subjects, by comparison with
compositions of conventional NSAIDs.
[0207] Thus, nanoparticulate nimesulide compositions of the
invention are particularly useful as an alternative to conventional
NSAIDs where such NSAIDs are contraindicated, for example in
patients with peptic ulcers, gastritis, regional enteritis,
ulcerative colitis, diverticulitis, or with a recurrent history of
gastrointestinal lesions; gastrointestinal bleeding; coagulation
disorders including anemia such as hypoprothrombinemia, hemophilia,
or other bleeding problems; kidney disease; or in patients prior to
surgery or patients taking anticoagulants.
[0208] Because of the rapid onset of therapeutic effect observed
with the compositions of the invention, these compositions have
particular advantages over prior conventional formulations for
treatment of acute COX-2 mediated disorders, especially for relief
of pain, for example in headache, including sinus headache and
migraine.
[0209] Nimesulide is also useful in treating and/or preventing, for
example, arthritic disorders, gastrointestinal conditions,
inflammatory conditions, pulmonary inflammation, opthalmic
diseases, central nervous systems disorders, pain,
inflammation-related cardiovascular disorders, angiogenesis-related
disorders, benign and malignant tumors, adenomatous polyps,
disorders of the female reproductive system such as endometriosis,
osteoporosis, dysmenorrhea, premature labor, asthma,
eosinophil-related disorders, pyrexia, bone resorption,
nephrotoxicity, hypotension, arthrosis, joint stiffness, kidney
disease, liver disease including hepatitis, acute mastitis,
diarrhea, colonic adenomas, bronchitis, allergic neuritis,
cytomegalovirus infectivity, apoptosis including HIV-induced
apoptosis, lumbago; skin-related conditions such as psoriasis,
eczema, acne, burns, dermatitis, and ultraviolet radiation damage
including sunburn; allergic rhinitis, respiratory distress
syndrome, and endotoxin shock syndrome. Nanoparticulate nimesulide
is also useful as an immunosuppressive agent.
[0210] Exemplary forms of arthritic disorders that can be treated
include, but are not limited to, osteoarthritis, rheumatoid
arthritis, spondyloarthropathies, gouty arthritis, juvenile
arthritis, gout, ankylosing spondylitis, systemic lupus
erythematosus, bursitis, tendinitis, myofascial pain, carpal tunnel
syndrome, fibromyalgia syndrome, infectious arthritis, psoriatic
arthritis, Reiter's syndrome, and scleroderma
[0211] Exemplary gastrointestinal conditions or ulcerative diseases
that can be treated include, but are not limited to, inflammatory
bowel disease, Crohn's disease, gastritis, irritable bowel
syndrome, ulcerative colitis, gastric ulcer, pathological but
non-malignant conditions such as hemangiomas, including infantile
hemaginomas, angiofibroma of the nasopharynx, and avascular
necrosis of bone.
[0212] Exemplary inflammation conditions that can be treated
include, but are not limited to, migraine headaches, periarteritis
nodosa, thyroiditis, aplastic anemia, Hodgkin's disease,
sclerodoma, rheumatic fever, type I diabetes, neuromuscular
junction disease including myasthenia gravis, white matter disease
including multiple sclerosis, sarcoidosis, nephrotic syndrome,
Behcet's syndrome, polymyositis, gingivitis, nephritis,
hypersensitivity, swelling occurring after injury including brain
edema, myocardial ischemia, post-operative inflammation including
that following ophthalmic surgery such as cataract surgery or
refractive surgery, and the like.
[0213] Exemplary pulmonary inflammation conditions that can be
treated include, but are not limited to, inflammation associated
with viral infections and cystic fibrosis, and in bone resorption
such as that associated with osteoporosis.
[0214] Exemplary opthalmic diseases or conditions that can be
treated include, but are not limited to, retinitis, conjunctivitis,
retinopathies, uveitis, ocular photophobia, acute injury to the eye
tissue, corneal graft rejection, ocular neovascularization, retinal
neovascularization including neovascularization following injury or
infection, diabetic retinopathy, macular degeneration, retrolental
fibroplasia, glaucoma, and neovascular glaucoma.
[0215] Exemplary central nervous system disorders that can be
treated include, but are not limited to, cortical dementias
including Alzheimer's disease, neurodegeneration, and central
nervous system damage resulting from stroke, ischemia, and trauma.
The term "treatment" in the present context includes partial or
total inhibition of dementias, including Alzheimer's disease,
vascular dementia, multi-infarct dementia, pre-senile dementia,
alcoholic dementia, and senile dementia.
[0216] Exemplary pain conditions that can be treated include, but
are not limited to, postoperative pain, pain resulting from battle
field wounds, dental pain, muscular pain, pain resulting from
cancer, headaches, including sinus headache and migraine, menstrual
cramps, and pain associated with inflammation.
[0217] Exemplary inflammation-related cardiovascular disorders that
can be treated or prevented using compositions of the invention
include, but are not limited to, vascular diseases, coronary artery
disease, aneurysm, vascular rejection, arteriosclerosis,
atherosclerosis including cardiac transplant atherosclerosis,
myocardial infarction, embolism, stroke, thrombosis including
venous thrombosis, angina including unstable angina, coronary
plaque inflammation, bacterial-induced inflammation including
Chlamydia-induced inflammation, viral induced inflammation, and
inflammation associated with surgical procedures such as vascular
grafting including coronary artery bypass surgery,
revascularization procedures including angioplasty, stent
placement, endarterectomy, or other invasive procedures involving
arteries, veins, and capillaries.
[0218] Exemplary angiogenesis-related disorders for which the
inventive compositions are useful include, but are not limited to,
inhibition of tumor angiogenesis. Such compositions also are useful
for treating neoplasia, including metastasis, benign and malignant
tumors, and neoplasia including cancer, such as colorectal cancer,
brain cancer, bone cancer, epithelial cell-derived neoplasia
(epithelial carcinoma) such as basal cell carcinoma,
adenocarcinoma, gastrointestinal cancer such as lip cancer, mouth
cancer, esophageal cancer, small bowel cancer, stomach cancer,
colon cancer, liver cancer, bladder cancer, pancreas cancer, ovary
cancer, cervical cancer, lung cancer, breast cancer, skin cancer
such as squamous cell and basal cell cancers, prostate cancer,
renal cell carcinoma, and other known cancers that effect
epithelial cells throughout the body. Neoplasias for which
compositions of the invention are contemplated to be particularly
useful are gastrointestinal cancer, Barrett's esophagus, liver
cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate
cancer, cervical cancer, lung cancer, breast cancer and skin
cancer. The nanoparticulate nimesulide compositions of the
invention can also be used to treat fibrosis that occurs with
radiation therapy.
[0219] The compositions of the invention can be used to treat
subjects having adenomatous polyps, including those with familial
adenomatous polyposis (FAP). Additionally, such compositions can be
used to prevent polyps from forming in patients at risk of FAP.
[0220] Because the nimesulide compositions of the invention inhibit
prostanoid-induced smooth muscle contraction by inhibiting
synthesis of contractile prostanoids, the compositions can be used
in the treatment of dysmenorrhea, premature labor, asthma, and
eosinophil-related disorders.
[0221] The compositions of the invention are also useful in
treating indications where anti-inflammatory agents,
anti-angiogenesis agents, antitumorigenic agents, immunosuppressive
agents, NSAIDs, COX-2 inhibitors, analgesic agents, anti-thrombotic
agents, narcotics, or antifebrile agents are typically used.
[0222] The following examples are provided to illustrate the
present invention. It should be understood, however, that the
invention is not to be limited to the specific conditions or
details described in these examples. Throughout the specification,
any and all references to a publicly available document, including
a U.S. patent, are specifically incorporated by reference.
EXAMPLE 1
[0223] The purpose of this example was to prepare a nanoparticulate
composition of nimesulide (Sigma, St. Louis, Mo.), a COX-2
inhibitor.
[0224] An aqueous solution of 1% (w/w) Plasdone.RTM. S-630
(International Specialty Products, Wayne, N.J.), which is a random
copolymer of vinyl acetate and vinyl pyrrolidone, was prepared by
dissolving 0.85 g of Plasdone.RTM. S-630 in 79.9 g of deionized
water. The surface stabilizer solution was combined with 4.25 g of
nimesulide (5% w/w) and PolyMill.TM.-200 Polystyrene Milling Media
(Dow Chemical, Midland, Mich.) and charged into the 150 cc batch
chamber of a DYNO.RTM.-Mill Type KDL media mill (Willy Bachofen AG,
Basel, Switzerland). The mill was operated for 1 hour at 4200 rpm
with chilled water (10.degree. C.) recirculated through the milling
chamber.
[0225] The process yielded a colloidal dispersion of nimesulide
with a mean particle size of 150 nm, a D50 of 124 nm, a D90 of 256
nm, and a D95 of 293 nm, as measured using a Horiba LA-910 Laser
Scattering Particle Size Distribution Analyzer ((Horiba
Instruments, Irvine, Calif.).
EXAMPLE 2
[0226] The purpose of this example was to prepare a nanoparticulate
composition of nimesulide.
[0227] An aqueous solution of 1% (w/w) Plasdone.RTM. S-630
(International Specialty Products, Wayne, N.J.) and 0.2% (w/w)
docusate sodium (DOSS; Cytec Industries Inc., West Paterson, N.J.)
was prepared by dissolving 0.85 g of Plasdone.RTM. S-630 and 0.17 g
of DOSS in 79.73 g of deionized water. The surface stabilizer
solution was combined with 4.25 g of nimesulide (5% w/w) and
PolyMill.TM.-200 Polystyrene Milling Media (Dow Chemical, Midland,
Mich.) and charged into the 150 cc batch chamber of a
DYNO.RTM.-Mill Type KDL media mill (Willy Bachofen AG, Basel,
Switzerland). The mill was operated for 2 hours at 4200 rpm with
chilled water (101C) recirculated through the milling chamber.
[0228] The process yielded a colloidal dispersion of nimesulide
with a mean particle size of 131 nm, a D50 of 111 nm, a D90 of 216
nm, and a D95 of 253 nm, as measured using a Horiba LA-910 Laser
Scattering Particle Size Distribution Analyzer ((Horiba
Instruments, Irvine, Calif.).
EXAMPLE 3
[0229] The purpose of this example was to prepare a nanoparticulate
composition of nimesulide.
[0230] An aqueous solution of 1% (w/w) Plasdone.RTM. S-630
(International Specialty Products, Wayne, N.J.) and 0.05% (w/w)
sodium lauryl sulfate (SLS) was prepared by dissolving 0.85 g of
Plasdone.RTM. S-630 and 0.04 g of SLS in 79.9 g of deionized water.
The surface stabilizer solution was combined with 4.25 g of
nimesulide (5% w/w) and PolyMill.TM.-200 Polystyrene Milling Media
(Dow Chemical, Midland, Mich.) and charged into the 150 cc batch
chamber of a DYNO.RTM.-Mill Type KDL media mill (Willy Bachofen AG,
Basel, Switzerland). The mill was operated for 2 hours at 4200 rpm
with chilled water (110.degree. C.) recirculated through the
milling chamber.
[0231] The process yielded a colloidal dispersion of nimesulide
with a mean particle size of 116 nm, a D50 of 104 nm, a D90 of 175
nm, and a D95 of 212 nm, as measured using a Horiba LA-910 Laser
Scattering Particle Size Distribution Analyzer ((Horiba
Instruments, Irvine, Calif.).
EXAMPLE 4
[0232] The purpose of this example was to prepare a nanoparticulate
composition of nimesulide.
[0233] An aqueous solution of 2% (w/w) hydroxypropylmethyl
cellulose (HPMC, Shin Etsu) was prepared by dissolving 1.7 g of
HPMC in 74.8 g of deionized water. The surface stabilizer solution
was combined with 8.5 g of nimesulide (10% w/w) and
PolyMill.TM.-200 Polystyrene Milling Media (Dow Chemical, Midland,
Mich.) and charged into the 150 cc batch chamber of a
DYNO.RTM.-Mill Type KDL media mill (Willy Bachofen AG, Basel,
Switzerland). The mill was operated for 2 hours at 4200 rpm with
chilled water (110.degree. C.) recirculated through the milling
chamber.
[0234] The process yielded a colloidal dispersion of nimesulide
with a mean particle size of 110 nm, a D50 of 103 nm, a D90 of 157
nm, and a D95 of 183 nm, as measured using a Horiba LA-910 Laser
Scattering Particle Size Distribution Analyzer ((Horiba
Instruments, Irvine, Calif.).
EXAMPLE 5
[0235] The purpose of this example was to prepare a nanoparticulate
composition of nimesulide.
[0236] An aqueous solution of 2% (w/w) tyloxapol (Organichem Corp.)
was prepared by dissolving 1.7 g of tyloxapol in 74.8 g of
deionized water. The surface stabilizer solution was combined with
8.5 g of nimesulide (10% w/w) and PolyMill.TM.-200 Polystyrene
Milling Media (Dow Chemical, Midland, Mich.) and charged into the
150 cc batch chamber of a DYNO.RTM.-Mill Type KDL media mill (Willy
Bachofen AG, Basel, Switzerland). The mill was operated for 2 hours
at 4200 rpm with chilled water (10.degree. C.) recirculated through
the milling chamber.
[0237] The process yielded a colloidal dispersion of nimesulide
with a mean particle size of 141 nm, a D50 of 127 nm, a D90 of 222
nm, and a D95 of 250 nm, as measured using a Horiba LA-910 Laser
Scattering Particle Size Distribution Analyzer ((Horiba
Instruments, Irvine, Calif.).
[0238] It will be apparent to those skilled in the art that various
modifications and variations can be made in the methods and
compositions of the present invention without departing from the
spirit or scope of the invention. Thus, it is intended that the
present invention cover the modifications and variations of this
invention provided they come within the scope of the appended
claims and their equivalents.
* * * * *